Therapeutic phenethylamine compositions and methods of use

Abstract

There are disclosed phenethylamine compounds, the use of such compounds in the treatment of diseases associated with a serotonin 5-HT2 receptor, pharmaceutical compositions such as tablet compositions and kits containing the compounds, methods of delivering the compounds in a mist via inhalation, and methods of treating diseases or disorders associated with a serotonin 5-HT2 receptor, such as central nervous system (CNS) disorders or psychological disorders with the disclosed compounds.

Description

CROSS-REFERENCE

[0001] This application claims priority to U.S. Provisional Application No. 63 / 268,019, filed on Feb. 15, 2022, U.S. Provisional Application No. 63 / 268,022, filed on Feb. 15, 2022, and U.S. Provisional Application No. 63 / 386,375, filed on Dec. 7, 2022, each incorporated by reference herein in their entireties.FIELD OF THE INVENTION

[0002] The present disclosure relates generally to phenethylamine compounds and, in some embodiments, to serotonin 5-HT2 receptor agonists and uses in the treatment of diseases associated with a 5-HT2 receptor.BACKGROUND OF THE INVENTION

[0003] The “background” description provided herein is for the purpose of generally presenting the context of the disclosure. Work of the presently named inventors, to the extent it is described in this background section, as well as aspects of the description which may not otherwise qualify as prior art at the time of filing, are neither expressly or impliedly admitted as prior art against the present invention.

[0004] There are three, closely related subtypes of serotonin 5-HT2 receptors (5-HT2Rs), 5-HT2A, 5-HT2B, and 5-HT2C, and they are primary targets of classic serotonergic psychedelics, such as lysergic acid diethylamide (LSD), psilocybin, and 2,5-dimethoxy-4-bromoamphetamine (DOB). Classic serotonergic psychedelics and entactogens have been actively investigated by the research and medical community to alleviate a multitude of central nervous system (CNS) disorders (Reiff, C. M., Richman, E. E., Nemeroff, C. B., Carpenter, L. L., Widge, A. S., Rodriguez, C. I., Kalin, N. H., and McDonald, W. M., 2020, Psychedelics and Psychedelic-Assisted Psychotherapy, Am J Psychiatry 177, 391-410), such as: (i) post-traumatic stress disorder (PTSD)(Jerome, L., Feduccia, A. A., Wang, J. B., Hamilton, S., Yazar-Klosinski, B., Emerson, A., Mithoefer, M. C., and Doblin, R., 2020, Long-term follow-up outcomes of MDMA-assisted psychotherapy for treatment of PTSD: a longitudinal pooled analysis of six phase 2 trials, Psychopharmacology (Berl) 237, 2485-2497), (ii) major depressive disorder (MDD), (iii) treatment-resistant depression (TRD)(Goldberg, S. B., Pace, B. T., Nicholas, C. R., Raison, C. L., and Hutson, P. R., 2020, The experimental effects of psilocybin on symptoms of anxiety and depression: A meta-analysis, Psychiatry Res 284, 112749), (iv) obsessive-compulsive disorder (OCD)(Moreno, F. A., Wiegand, C. B., Taitano, E. K., and Delgado, P. L., 2006, Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive-compulsive disorder, J Clin Psychiatry 67, 1735-1740), (v) social anxiety disorder (ClinicalTrials.gov, number NCT02008396), (vi) substance use disorders, including but not limited to alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, and cocaine use disorder, (vii) anorexia nervosa, (viii) bulimia nervosa (ClinicalTrials.gov, numbers NCT04454684 and NCT04052568), (ix) Alzheimer's disease (ClinicalTrials.gov, number NCTO4123314), and (x) cluster headache and migraine (Nichols, D. E., 2016, Psychedelics, Pharmacol Rev 68, 264-355; Johnson, M. W., Hendricks, P. S., Barrett, F. S., and Griffiths, R. R., 2019, Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function, Pharmacol Ther 197, 83-102; Sewell, R. A., Halpern, J. H., and Pope, H. G., Jr., 2006, Response of cluster headache to psilocybin and LSD, Neurology 66, 1920-1922; ClinicalTrials.gov, number NCTO4218539).

[0005] These drugs have also been investigated to alleviate conditions of the autonomic nervous system (ANS), including pulmonary disorders (e.g., asthma and chronic obstructive pulmonary disorder (COPD) and cardiovascular disorders (e.g., atherosclerosis), among others (Nichols, D. E., Johnson, M. W., and Nichols, C. D., 2017, Psychedelics as Medicines: An Emerging New Paradigm, Clin Pharmacol Ther 101, 209-219; Flanagan, T. W., Sebastian, M. N., Battaglia, D. M., Foster, T. P., Cormier, S. A., and Nichols, C. D., 2019, 5-HT2 receptor activation alleviates airway inflammation and structural remodeling in a chronic mouse asthma model, Life Sci 236, 116790; Flanagan, T. W., Sebastian, M. N., Battaglia, D. M., Foster, T. P., Maillet, E. L., and Nichols, C. D., 2019, Activation of 5-HT2 Receptors Reduces Inflammation in Vascular Tissue and Cholesterol Levels in High-Fat Diet-Fed Apolipoprotein E Knockout Mice, Sci Rep 9, 13444; Sexton, J. D., Nichols, C. D., and Hendricks, P. S., 2019, Population Survey Data Informing the Therapeutic Potential of Classic and Novel Phenethylamine, Tryptamine, and Lysergamide Psychedelics, Front Psychiatry 10, 896).

[0006] Some studies have advanced into Phase III trials, for example the use of 3,4-methylenedioxymethamphetamine (MDMA) for the treatment of PTSD (Feduccia, A. A., Jerome, L., Yazar-Klosinski, B., Emerson, A., Mithoefer, M. C., and Doblin, R., 2019, Breakthrough for Trauma Treatment: Safety and Efficacy of MDMA-Assisted Psychotherapy Compared to Paroxetine and Sertraline, Front Psychiatry 10, 650), and phase 1 trials of 3,4,5-trimethoxyphenethylamine (mescaline) have begun (ClinicalTrials.gov, number NCT04227756).

[0007] Mechanistically, the therapeutic effects of psychedelic phenethylamines are thought to be mediated by their interaction with serotonin (5-HT) receptors, particularly 5-HT2A receptors, though other targets, including the 5-HT1A receptor may also be involved (Nichols, D. E., 2016, Psychedelics, Pharmacol Rev 68, 264-355; Canal, C. E., 2018, Serotonergic Psychedelics: Experimental Approaches for Assessing Mechanisms of Action, Handb Exp Pharmacol 252, 227-260). A contribution from the 5-HT2C receptor may be responsible for the reported anti-addictive properties of classic psychedelics (Canal, C. E., and Murnane, K. S., 2017, The serotonin 5-HT2C receptor and the non-addictive nature of classic hallucinogens, J Psychopharmacol 31, 127-143). The effects of entactogen phenethylamines are mediated primarily by their interaction with monoamine transporters, particular the serotonin (SERT) and dopamine (DAT) transporters (Jayanthi, L. D., and Ramamoorthy, S., 2005, Regulation of monoamine transporters: influence of psychostimulants and therapeutic antidepressants, AAPS J 7, E728-738).

[0008] Safety aspects of psychedelics and entactogens remain a key challenge for clinical applications (Hasler, F., Grimberg, U., Benz, M. A., Huber, T., and Vollenweider, F. X., 2004, Acute psychological and physiological effects of psilocybin in healthy humans: a double-blind, placebo-controlled dose-effect study, Psychopharmacology (Berl) 172, 145-156; Carbonaro, T. M., Bradstreet, M. P., Barrett, F. S., MacLean, K. A., Jesse, R., Johnson, M. W., and Griffiths, R. R., 2016, Survey study of challenging experiences after ingesting psilocybin mushrooms: Acute and enduring positive and negative consequences, J Psychopharmacol 30, 1268-1278; Garcia-Romeu, A., Kersgaard, B., and Addy, P. H., 2016, Clinical applications of hallucinogens: A review, Exp Clin Psychopharmacol 24, 229-268; Morgan, L., 2020, MDMA-assisted psychotherapy for people diagnosed with treatment-resistant PTSD: what it is and what it isn't, Ann Gen Psychiatry 19, 33; Schenk, S., and Newcombe, D., 2018, Methylenedioxymethamphetamine (MDMA) in Psychiatry: Pros, Cons, and Suggestions, J Clin Psychopharmacol 38, 632-638).

[0009] Clearly, a safe therapeutic window for this class of drugs is very narrow, because of cardiovascular complications associated with prolonged, increased serotonin release and 5-HT2B stimulation (Huang, X.-P., Setola, V., Yadav, P. N., Allen, J. A., Rogan, S. C., Hanson, B. J., Revankar, C., Robers, M., Doucette, C., and Roth, B. L., 2009, Parallel Functional Activity Profiling Reveals Valvulopathogens Are Potent 5-Hydroxytryptamine(2B) Receptor Agonists: Implications for Drug 25 Safety Assessment, Molecular Pharmacology 76, 710-722; Rothman, R. B., and Baumann, M. H., 2009, Serotonergic drugs and valvular heart disease, Expert Opin Drug Saf 8, 317-329), depressive after-effects associated with depletion of central serotonin levels (Parrott, A. C., 2014, The potential dangers of using MDMA for psychotherapy, J Psychoactive Drugs 46, 37-43), and numerous other acute adverse effects, including anxiety, fear, tachycardia, hypertension, increased body temperature, nausea and vomiting, with many acute adverse effects being attributed to high drug concentrations (“spiking”) in the blood shortly after oral administration (Meyer, J. S., 2013, 3,4-methylenedioxymethamphetamine (MDMA): current perspectives, Subst Abuse Rehabil 4, 83-99; Baylen, C. A., and Rosenberg, H., 2006, A review of the acute subjective effects of MDMA / ecstasy, Addiction 101, 933-947; Shulgin, A., and Shulgin, Ann., 1991, Pihkal: a chemical love story, Transform Press, Berkeley, CA; Barrett, F. S., Bradstreet, M. P., Leoutsakos, J. S., Johnson, M. W., and Griffiths, R. R., 2016, The Challenging Experience Questionnaire: Characterization of challenging experiences with psilocybin mushrooms, J Psychopharmacol 30, 1279-1295). Many psychedelics and entactogens are also long acting, and thus require full day supervision considering their narrow therapeutic window, which is a major impediment to their clinical use.

[0010] One class of psychedelic phenethylamines is the 2C—X family of phenethylamines (phenethylamines containing 2,4,5 substitution, with methoxy groups at the 2 and 5 positions of the phenyl group). Members of this class, such as 2,5-dimethoxy-4-bromophenethylamine (2C—B), may be used to treat sexual dysfunctions (Shulgin, A., and Shulgin, Ann., 1991, Pihkal: a chemical love story, Transform Press, Berkeley, CA), as well as neuropsychiatric conditions, and induce changes in perception, cognition, emotion, and mood that may underlie its reported neuropsychotherapeutic benefits (Johnson, M. W., Hendricks, P. S., Barrett, F. S., and Griffiths, R. R., 2019, Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function, Pharmacol Ther 197, 83-102).

[0011] However, wider clinical testing and finding practical treatment protocols for 2C—X compounds is challenged by the following factors: 1) poor oral bioavailability; 2) low brain penetration; 3) delayed effects from oral administration; 4) therapeutic effects requiring high doses; 5) acute psychiatric adverse events (AE), such as fear, anxiety, and paranoia, cardiovascular events including tachycardia and hypertension, and gastrointestinal effects including nausea; and 6) toxicity. These properties are thought to be due to rapid first-pass metabolism through deamination / oxidation by monoamine oxidases (MAO), MAO-A and MAO-B and O-dealkylation by cytochrome P450 enzymes such as CYP2D6, and also to their relatively hydrophilic nature (e.g., 2,4,5-trimethoxphenethylamine (2C—O) possesses a logP value of 0.98; ChemDraw) which limits distribution to the brain (Suzuki, O., Katsumata, Y., and Oya, M., 1981, Oxidation of beta-phenylethylamine by both types of monoamine oxidase: examination of enzymes in brain and liver mitochondria of eight species, J Neurochem 36, 1298-1301; Monte, A. P., Marona-Lewicka, D., Parker, M. A., Wainscott, D. B., Nelson, D. L., and Nichols, D. E., 1996, Dihydrobenzofuran analogues of hallucinogens. 3. Models of 4-substituted (2,5-dimethoxyphenyl)alkylamine derivatives with rigidified methoxy groups, J Med Chem 39, 2953-2961; Monte, A. P., Waldman, S. R., Marona-Lewicka, D., Wainscott, D. B., Nelson, D. L., Sanders-Bush, E., and Nichols, D. E., 1997, Dihydrobenzofuran analogues of hallucinogens. 4. Mescaline derivatives, J Med Chem 40, 2997-3008). For example, 2,4,5-trimethoxphenethylamine (2C—O) is inactive after oral administration (Shulgin, A. T., 1978, Psychotomimetic Drugs: Structure-activity relationships. Chapter 6, In Handbook of psychopharmacology, V.11-Stimulants, pp 243-333, Plenum Press, New York).

[0012] The limitations of current 2C—X compounds and formulations thereof, and other psychedelic and entactogen phenethylamines, are apparent—and it has proven difficult to control drug exposure and maintain drug concentrations in the safe and efficacious range.SUMMARY OF THE INVENTION

[0013] In view of the forgoing, there is a need for novel phenethylamine compounds, e.g., of the 2C—X variety, which have improved pharmacokinetic properties—that are bioavailable, brain penetrable, have fast onset, and are short acting—and which demonstrate enhanced activity while minimizing psychiatric adverse events and toxicity. There is a further need for efficient, more convenient, and controllable phenethylamine formulations that afford no neurologically toxic (e.g., psychotomimetic toxic) plasma concentration.

[0014] Accordingly, it is one object of the present invention to provide novel compounds that meet these criteria.

[0015] It is another object of the present disclosure to provide novel pharmaceutical compositions which contain the compounds.

[0016] It is another object of the present disclosure to provide novel methods of treating a subject with a disease or disorder e.g., those associated with a serotonin 5-HT2 receptor, with the compounds.

[0017] It is another object of the present disclosure to provide novel tablet compositions, such as single-layer orally administered tablet compositions, containing the compounds.

[0018] It is another object of the present disclosure to provide novel kits containing formulations of the compounds for use in treatment.

[0019] It is yet another object of the present disclosure to provide novel methods of delivering the compounds in an aerosol, preferably a mist, via inhalation, such as for the treatment of a central nervous system (CNS) disorder or psychological disorder.

[0020] It is yet another object of the invention to provide a novel use of the compounds for treating a subject with a disease or disorder associated with a serotonin 5-HT2 receptor, such as a central nervous system (CNS) disorder or psychological disorder.

[0021] These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery of novel 2C—X type phenethylamine compounds (e.g., compounds of Formula (I) through (VII)), including those with site-specific modifications (e.g., deuteration / fluorination) which maintain preferential binding to G-protein coupled receptors (GPCRs), e.g., 5-HT2 receptors, have improved exposure (e.g., prevent high drug concentrations (spiking) observed acutely after administration), and possess advantageous enzymatic degradation profiles for improved bioavailability, brain penetration, and prevention / reduction of toxic metabolite formation.

[0022] Thus, the present invention provides:

[0023] (1) A compound having a structure of Formula (I):or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof,

[0025] wherein:

[0026] X1 and X2 are independently hydrogen or deuterium;

[0027] Y1 and Y2 are independently hydrogen or deuterium;

[0028] R3 is hydrogen or deuterium;

[0029] R4 is halogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C3-C10 cycloalkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, —ORb, or —SRb;

[0030] R6 and R7 are independently hydrogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; or alternatively R6 and R7 together with the nitrogen atom attached thereto are optionally joined to form a substituted or unsubstituted heterocycloalkyl;

[0031] each Ra is independently a substituted or unsubstituted C1-C6 alkyl; and

[0032] Rb is hydrogen, deuterium, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, or a substituted or unsubstituted C3-C10 cycloalkyl;

[0033] with the proviso that at least one of X1, X2, Y1, Y2, R3, R4, R6, R7, and Ra comprises deuterium and / or R4 is selected from the group consisting of —SCF3, —SCF2H, —SCFH2, —SCH2CH2CF3, —SCH2CH2CF2H, —SCH2CH2CFH2, —SCH2CF2CF2H, —OCF3, —OCF2H, —OCFH2, —OCH2CH2CF3, —OCH2CH2CF2H, —OCH2CH2CFH2, —OCH2CF2CF2H, -cyclopentyl (—C5H9), and -A(CF2)m(CH2)nQ, wherein A is S, O, CH2, or CF2, m is 0 to 3, n is 0 to 6, and Q is —C≡CH or —C≡N.

[0034] (2) The compound of (1), wherein Y1 and Y2 are hydrogen.

[0035] (3) The compound of (1) or (2), wherein R3 is hydrogen.

[0036] (4) The compound of any one of (1) to (3), wherein X1 and X2 are hydrogen.

[0037] (5) The compound of any one of (1) to (3), wherein X1 and X2 are deuterium.

[0038] (6) The compound of any one of (1) to (5), wherein each Ra is —CH3 or —CD3.

[0039] (7) The compound of any one of (1) to (6), wherein R4 is —SMe, —SCD3, —SCF3, —SCF2H, —SCFH2, —SCH2CH2CF3, —SCH2CH2CF2H, —SCH2CH2CFH2, —SCH2CF2CF2H, —SCH2C≡CH, —SC≡CH, —SCF2C≡CH, —SCH2CH2CH2C≡CH, —SCF2CH2CH2C≡CH, —SEt, —Sn—Pr, -Me, —CD3, —CF3, -t-Bu, —C(CD3)3, -cyclopentyl, —OMe, —OCD3, —OCF3, —OCF2H, —OCFH2, —OCH2CH2CF3, —OCH2CH2CF2H, —OCH2CH2CFH2, —OCH2CF2CF2H, —OCH2C≡CH, —OC≡CH, —CH2CH2CH2CH2C≡CH, —CF2CH2CH2CH2C≡CH, —Cl, —I, or —Br.

[0040] (8) The compound of (1), having a structure of Formula (II):or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof,

[0042] wherein:

[0043] X1 and X2 are independently hydrogen or deuterium;

[0044] Y1 and Y2 are independently hydrogen or deuterium;

[0045] R4 is halogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C3-C10 cycloalkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, —ORb, or —SRb; and

[0046] Rb is hydrogen, deuterium, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, or a substituted or unsubstituted C3-C10 cycloalkyl.

[0047] (9) The compound of (8), wherein X1 and X2 are hydrogen.

[0048] (10) The compound of (8) or (9), wherein R4 is —SMe, —SCD3, —SCF3, —SCF2H, —SCFH2, —SCH2CH2CF3, —SCH2CH2CF2H, —SCH2CH2CFH2, —SCH2CF2CF2H, —SCH2C≡CH, —SC≡CH, —SCF2C≡CH, —SCH2CH2CH2C≡CH, —SCF2CH2CH2C≡CH, —SEt, —Sn—Pr, -Me, —CD3, —CF3, -t-Bu, —C(CD3)3, -cyclopentyl, —OMe, —OCD3, —OCF3, —OCF2H, —OCFH2, —OCH2CH2CF3, —OCH2CH2CF2H, —OCH2CH2CFH2, —OCH2CF2CF2H, —OCH2C≡CH, —OC≡CH, —CH2CH2CH2CH2C≡CH, —CF2CH2CH2CH2C≡CH, —Cl, —I, or —Br.

[0049] (11) The compound of any one of (8) to (10), wherein R4 is —SMe, —SCF3, —SCF2H, -Me, —OCD3, —CF3, -t-Bu, or -cyclopentyl.

[0050] (12) The compound of (1), having a structure of Formula (III):or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof,

[0052] wherein:

[0053] X1 and X2 are independently hydrogen or deuterium;

[0054] Y1 and Y2 are independently hydrogen or deuterium;

[0055] R4 is a C1-C6 alkyl substituted with one or more deuterium, a C3-C10 cycloalkyl substituted with one or more deuterium, —ORb, or —SRb;

[0056] each Ra is independently a substituted or unsubstituted C1-C6 alkyl; and

[0057] Rb is a C1-C6 alkyl substituted with one or more deuterium or a C3-C10 cycloalkyl substituted with one or more deuterium.

[0058] (13) The compound of (12), wherein X1 and X2 are hydrogen and each Ra is —CH3.

[0059] (14) The compound of (12) or (13), wherein R4 is —SCD3, —CD3, —C(CD3)3, or —OCD3.

[0060] (15) The compound of (1), having a structure of Formula (IV):or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof,

[0062] wherein:

[0063] Y1 and Y2 are independently hydrogen or deuterium;

[0064] R4 is halogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C3-C10 cycloalkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, —ORb, or —SRb;

[0065] each Ra is independently a substituted or unsubstituted C1-C6 alkyl; and

[0066] Rb is hydrogen, deuterium, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, or a substituted or unsubstituted C3-C10 cycloalkyl.

[0067] (16) The compound of (1), having a structure of Formula (V):or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof,

[0069] wherein:

[0070] X1 and X2 are independently hydrogen or deuterium;

[0071] Y1 and Y2 are independently hydrogen or deuterium;

[0072] R4 is halogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C3-C10 cycloalkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, —ORb, or —SRb;

[0073] R6 is hydrogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl;

[0074] R7 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl;

[0075] or alternatively R6 and R7 together with the nitrogen atom attached thereto are optionally joined to form a substituted or unsubstituted heterocycloalkyl;

[0076] each Ra is independently a substituted or unsubstituted C1-C6 alkyl; and

[0077] Rb is hydrogen, deuterium, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, or a substituted or unsubstituted C3-C10 cycloalkyl;

[0078] with the proviso that at least one of X1, X2, Y1, Y2, R3, R4, R6, R7, and Ra comprises deuterium and / or R4 is selected from the group consisting of —SCF3, —SCF2H, —SCFH2, —SCH2CH2CF3, —SCH2CH2CF2H, —SCH2CH2CFH2, —SCH2CF2CF2H, —OCF3, —OCF2H, —OCFH2, —OCH2CH2CF3, —OCH2CH2CF2H, —OCH2CH2CFH2, —OCH2CF2CF2H, -cyclopentyl (—C5H9), and -A(CF2)m(CH2)nQ, wherein A is S, O, CH2, or CF2, m is 0 to 3, n is 0 to 6, and Q is —C≡CH or —C≡N.

[0079] (17) The compound of (16), wherein R6 is hydrogen, and R7 is an unsubstituted C1-C6 alkyl, a C1-C6 alkyl substituted with one or more deuterium atoms, a C1-C6 alkyl substituted with one or more fluorine atoms, or a C1-C6 alkyl substituted with a substituted or unsubstituted cycloalkyl.

[0080] (18) The compound of any one of (1) to (17), which is selected from the group consisting ofor a pharmaceutically acceptable salt, solvate, or prodrug thereof.(19) The compound of any one of (1) to (18), wherein the compound is an agonist of a serotonin 5-HT2 receptor.(20) The compound of any one of (1) to (19), wherein the compound is an agonist of a serotonin 5-HT2A receptor.(21) A pharmaceutical composition, comprising the compound of any one of (1) to (20) and a pharmaceutically acceptable excipient.(22) The pharmaceutical composition of (21), wherein the compound is present in the pharmaceutical composition at a purity of at least 50% by weight based on a total weight of isotopologues of the compound present in the pharmaceutical composition.(23) The pharmaceutical composition of (21) or (22), wherein any position in the compound having deuterium has a minimum deuterium incorporation of at least 50 atom % at the site of deuteration.(24) The pharmaceutical composition of any one of (21) to (23), which is substantially free of other isotopologues of the compound.

[0087] (25) The pharmaceutical composition of any one of (21) to (24), which is formulated for oral administration.

[0088] (26) The pharmaceutical composition of any one of (21) to (24), which is formulated for administration via inhalation.

[0089] (27) A method of treating a subject with a disease or disorder associated with a serotonin 5-HT2 receptor, the method comprising:

[0090] administering to the subject a therapeutically effective amount of the compound of any one of (1) to (20).

[0091] (28) The method of (27), wherein the disease or disorder associated with a serotonin 5-HT2 receptor is a neuropsychiatric disease or disorder or an inflammatory disease or disorder.

[0092] (29) The method of (27), wherein the disease or disorder associated with a serotonin 5-HT2 receptor is a central nervous system (CNS) disorder.

[0093] (30) The method of (29), wherein the central nervous system (CNS) disorder is selected from the group consisting of post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation, suicidal behavior, major depressive disorder with suicidal ideation or suicidal behavior, non-suicidal self-injury disorder (NSSID), a bipolar disorder and related disorders, cyclothymic disorder, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social anxiety disorder, a substance use disorder including alcohol use disorder, anorexia nervosa, bulimia nervosa, binge eating disorder, Alzheimer's disease, cluster headache and migraine, attention deficit hyperactivity disorder (ADHD), pain, aphantasia, childhood-onset fluency disorder, major neurocognitive disorder, mild neurocognitive disorder, sexual dysfunction, chronic fatigue syndrome, Lyme disease, and obesity.

[0094] (31) The method of (29), wherein the central nervous system (CNS) disorder is pain.

[0095] (32) The method of (29), wherein the central nervous system (CNS) disorder is sexual dysfunction.

[0096] (33) The method of (27), wherein the disease or disorder associated with a serotonin 5-HT2 receptor is an autonomic nervous system (ANS) disorder.

[0097] (34) The method of (33), wherein the autonomic nervous system (ANS) disorder is a pulmonary disorder or a cardiovascular disorder.

[0098] (35) The method of any one of (27) to (34), wherein the compound is administered orally, sublingually, buccally, topically, via injection, or via inhalation.

[0099] (36) A single-layer orally administered tablet composition comprising the compound of any one of (1) to (20), and a polymer.

[0100] (37) The single-layer orally administered tablet composition of (36), wherein the composition is adapted for maximum sustained release.

[0101] (38) The single-layer orally administered tablet composition of (36) or (37), wherein the tablet composition comprises a combination of (i) a water-insoluble neutrally charged non-ionic matrix; (ii) a polymer carrying one or more negatively charged groups; and (iii) the compound.

[0102] (39) The single-layer orally administered tablet composition of (38), wherein the water-insoluble neutrally charged non-ionic matrix is selected from a cellulose-based polymer, alone or enhanced by mixing with components selected from the group consisting of starches; waxes; neutral gums; polymethacrylates; PVA; PVA / PVP blends; and mixtures thereof.

[0103] (40) The single-layer orally administered tablet composition of (39), wherein the cellulose-based polymer is hydroxypropyl methylcellulose (HPMC).

[0104] (41) The single-layer orally administered tablet composition of (38), wherein the polymer carrying one or more negatively charged groups is selected from the group consisting of polyacrylic acid, polylactic acid, polyglycolic acid, polymethacrylate carboxylate, a cation-exchange resin, a clay, a zeolite, hyaluronic acid, an anionic gum, salts thereof, and mixtures thereof.

[0105] (42) The single-layer orally administered tablet composition of (41), wherein the anionic gum is selected from the group consisting of a naturally occurring material and a semi-synthetic material.

[0106] (43) The single-layer orally administered tablet composition of (42), wherein the naturally occurring material is selected from the group consisting of alginic acid, pectin, xanthan gum, carrageenan, locust bean gum, gum arabic, gum karaya, guar gum, and gum tragacanth.

[0107] (44) The single-layer orally administered tablet composition of (42) or (43), wherein the semi-synthetic material is selected from the group consisting of carboxymethyl-chitin and cellulose gum.

[0108] (45) The single-layer orally administered tablet composition of any one of (36) to (44), comprising a therapeutically effective amount of the compound for the treatment of pain.

[0109] (46) The single-layer orally administered tablet composition of any one of (36) to (44), comprising a therapeutically effective amount of the compound for the treatment of brain injury.

[0110] (47) The single-layer orally administered tablet composition of any one of (36) to (44), comprising a therapeutically effective amount of the compound for the treatment of depression.

[0111] (48) The single-layer orally administered tablet composition of any one of (36) to (44), comprising a therapeutically effective amount of the compound for use in treating a disease or disorder associated with a serotonin 5-HT2 receptor.

[0112] (49) The single-layer orally administered tablet composition of (48), wherein the disease or disorder is a central nervous system (CNS) disorder selected from the group consisting of post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation, suicidal behavior, major depressive disorder with suicidal ideation or suicidal behavior, non-suicidal self-injury disorder (NSSID), bipolar and related disorders including bipolar I disorder, bipolar II disorder, cyclothymic disorder, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social anxiety disorder, substance use disorders including alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, and cocaine use disorder, anorexia nervosa, bulimia nervosa, binge eating disorder, Alzheimer's disease, cluster headache and migraine, attention deficit hyperactivity disorder (ADHD), pain and neuropathic pain, aphantasia, childhood-onset fluency disorder, major neurocognitive disorder, mild neurocognitive disorder, sexual dysfunction, chronic fatigue syndrome, Lyme disease, and obesity.

[0113] (50) The single-layer orally administered tablet composition of (48), wherein the disease or disorder is a condition of the autonomic nervous system (ANS).

[0114] (51) The single-layer orally administered tablet composition of (48), wherein the disease or disorder is a pulmonary disorder.

[0115] (52) The single-layer orally administered tablet composition of (48), wherein the disease or disorder is a cardiovascular disorder.

[0116] (53) The single-layer orally administered tablet composition of any one of (36) to (52), wherein the composition achieves a combined concentration of the compound in plasma in the range of 10-500 ng / ml, and maintains this concentration for a duration of release.

[0117] (54) The single-layer orally administered tablet composition of any one of (36) to (53), wherein the polymer comprises one or more negatively charged groups.

[0118] (55) A tablet composition formulated for oral administration comprising the compound of any one of (1) to (20), and a polymer.

[0119] (56) The tablet composition of (55), wherein the polymer comprises one or more negatively charged groups.

[0120] (57) The tablet composition of (55), wherein the polymer comprises one or more acid groups.

[0121] (58) The tablet composition of any one of (55) to (57), wherein the polymer comprises a water-insoluble neutrally charged non-ionic matrix.

[0122] (59) The tablet composition of (58), wherein the water-insoluble neutrally charged non-ionic matrix is selected from a cellulose-based polymer, alone or enhanced by mixing with components selected from the group consisting of starches; waxes; neutral gums; polymethacrylates; PVA; PVA / PVP blends; and mixtures thereof.

[0123] (60) The tablet composition of (59), wherein the cellulose-based polymer is hydroxypropyl methylcellulose (HPMC).

[0124] (61) A kit for the treatment of a subject comprising 1) a single-layer orally administered tablet composition of any one of (36) to (54), and 2) instructions for use in the treatment of pain.

[0125] (62) The kit of (61), wherein the polymer comprises one or more negatively charged groups.

[0126] (63) A kit for the treatment of a subject comprising 1) a single-layer orally administered tablet composition of any one of (36) to (54), and 2) instructions for use in the treatment of brain injury.

[0127] (64) The kit of (63), wherein the polymer comprises one or more negatively charged groups.

[0128] (65) A kit for the treatment of a subject comprising 1) a single-layer orally administered tablet composition of any one of (36) to (54) and 2) instructions for use in the treatment of depression.

[0129] (66) The kit of (65), wherein the polymer comprises one or more negatively charged groups.

[0130] (67) A kit for the treatment of a subject comprising 1) a single-layer orally administered tablet composition of any one of (36) to (54) and 2) instructions for use in the treatment of a disease or disorder associated with a serotonin 5-HT2 receptor.

[0131] (68) The kit of (67), wherein the polymer comprises one or more negatively charged groups.

[0132] (69) A method of delivering a compound of any one of (1) to (20) to a subject in need thereof comprising administering the compound dissolved in a liquid phase of a mist via inhalation.

[0133] (70) The method of (69), wherein the compound is delivered to the subject's central nervous system.

[0134] (71) The method of (69) or (70), wherein the compound is delivered with air, oxygen, or a mixture of helium and oxygen.

[0135] (72) The method of any one of (69) to (71), wherein the compound is delivered with a mixture of helium and oxygen.

[0136] (73) The method of (72), wherein the mixture of helium and oxygen is heated to about 50° C. to about 60° C.

[0137] (74) The method of (72) or (73), wherein the helium is present in the mixture of helium and oxygen at about 50 to 90% and the oxygen is present in the mixture of helium and oxygen at about 10 to 50%.

[0138] (75) The method of any one of (72) to (74), further comprising administering a pretreatment inhalation therapy prior to administration of the mixture of helium and oxygen and the compound.

[0139] (76) The method of (75), wherein the pretreatment comprises administering via inhalation a mixture of helium and oxygen heated to about 90° C. to about 120° C. to the subject.

[0140] (77) The method of (69) to (76), further comprising (i) administering via inhalation a mixture of helium and oxygen heated to about 90° C. to about 120° C. to the subject, and (ii) administering via inhalation to the subject a mist comprising helium and oxygen heated to about 50° C. to about 60° C. and the compound.

[0141] (78) The method of (77), further comprising repeating steps (i) and (ii) at least one time.

[0142] (79) The method of any one of (69) to (78), wherein the compound is delivered to the subject's central nervous system with an improvement in drug bioavailability by at least 25% as compared to oral delivery, increased Cmax by at least 25% as compared to oral delivery, reduced Tmax by at least 50% as compared to oral delivery, or a combination thereof.

[0143] (80) A method of treating a central nervous system (CNS) disorder or psychological disorder comprising administering, via inhalation, a compound of any one of (1) to (20) dissolved in a mist.

[0144] (81) The method of (80), wherein the compound is delivered with air, oxygen, or a mixture of helium and oxygen.

[0145] (82) The method of (80) or (81), wherein the compound is delivered with the mixture of helium and oxygen, and the mixture of helium and oxygen is heated to about 50° C. to about 60° C. prior to administering the compound to the subject.

[0146] (83) The method of any one of (80) to (82), wherein the CNS disorder is post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation, suicidal behavior, major depressive disorder with suicidal ideation or suicidal behavior, non-suicidal self-injury disorder (NSSID), bipolar and related disorders including bipolar I disorder, bipolar II disorder, cyclothymic disorder, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social anxiety disorder, substance use disorders including alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, and cocaine use disorder, anorexia nervosa, bulimia nervosa, binge eating disorder, Alzheimer's disease, cluster headache and migraine, attention deficit hyperactivity disorder (ADHD), pain and neuropathic pain, aphantasia, childhood-onset fluency disorder, major neurocognitive disorder, mild neurocognitive disorder, sexual dysfunction, chronic fatigue syndrome, Lyme disease, or obesity.

[0147] (84) A transdermal patch, comprising the compound of any one of (1) to (20).

[0148] (85) The transdermal patch of (84), further comprising a pressure sensitive adhesive layer, a backing, and a release liner.

[0149] (86) The transdermal patch of (85), wherein the compound is uniformly distributed throughout the pressure sensitive adhesive layer.

[0150] (87) The transdermal patch of any one of (84) to (86), comprising 5 mg to 25 mg of the compound.

[0151] (88) A method of treating a subject with a disease or disorder associated with a serotonin 5-HT2 receptor, the method comprising: administering to the subject, via the transdermal patch of any one of (84) to (87), a therapeutically effective amount of the compound.

[0152] (89) The method of (88), wherein the disease or disorder associated with a serotonin 5-HT2 receptor is a neuropsychiatric disease or disorder or an inflammatory disease or disorder.

[0153] (90) The method of (88), wherein the disease or disorder associated with a serotonin 5-HT2 receptor is a central nervous system (CNS) disorder.

[0154] (91) The method of (90), wherein the central nervous system (CNS) disorder is selected from the group consisting of post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation, suicidal behavior, major depressive disorder with suicidal ideation or suicidal behavior, non-suicidal self-injury disorder (NSSID), a bipolar disorder and related disorders, cyclothymic disorder, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social anxiety disorder, a substance use disorder, anorexia nervosa, bulimia nervosa, binge eating disorder, Alzheimer's disease, cluster headache and migraine, attention deficit hyperactivity disorder (ADHD), pain, aphantasia, childhood-onset fluency disorder, major neurocognitive disorder, mild neurocognitive disorder, sexual dysfunction, chronic fatigue syndrome, Lyme disease, and obesity.

[0155] (92) The method of (88), wherein the disease or disorder associated with a serotonin 5-HT2 receptor is an autonomic nervous system (ANS) disorder.

[0156] (93) The method of (92), wherein the autonomic nervous system (ANS) disorder is a pulmonary disorder or a cardiovascular disorder.

[0157] (94) The method of any one of (88) to (93), wherein 5 mg to 25 mg of the compound is administered to the subject over a 4 to 72 hour period.

[0158] (95) The method of any one of (88) to (94), wherein a serotonergic, but sub-psychoactive concentration of the compound is administered.

[0159] (96) A method of treating a subject with a disease or disorder associated with a serotonin 5-HT2 receptor, the method comprising: administering to the subject transdermally, subcutaneously, or intramuscularly, via an automatic injection device, a therapeutically effective amount of the compound of any one of (1) to (20).

[0160] (97) A compound having a structure of Formula (VI):or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof,

[0162] wherein:

[0163] X1 and X2 are independently hydrogen or deuterium;

[0164] Y1 and Y2 are independently hydrogen or deuterium;

[0165] R3 is hydrogen or deuterium;

[0166] R6 and R7 are independently hydrogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; or alternatively R6 and R7 together with the nitrogen atom attached thereto are optionally joined to form a substituted or unsubstituted heterocycloalkyl;

[0167] each Ra is independently a substituted or unsubstituted C1-C6 alkyl; and

[0168] each Rb is independently a substituted or unsubstituted C1-C2 alkyl; or alternatively two Rbs together with the carbon atom attached thereto are optionally joined to form a substituted or unsubstituted cycloalkyl.

[0169] (98) The compound of (97), which is selected from the group consisting ofor a pharmaceutically acceptable salt, solvate, or prodrug thereof.(99) A pharmaceutical composition, comprising the compound of (97) or (98) and a pharmaceutically acceptable excipient.

[0171] (100) A method of treating a subject with a disease or disorder associated with a serotonin 5-HT2 receptor, the method comprising:

[0172] administering to the subject a therapeutically effective amount of the compound of (97) or (98).

[0173] (101) A compound having a structure of Formula (VII):or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof,

[0175] wherein:

[0176] X1 and X2 are independently hydrogen or deuterium;

[0177] Y1 and Y2 are independently hydrogen or deuterium;

[0178] R6 is hydrogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl;

[0179] R7 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl;

[0180] or alternatively R6 and R7 together with the nitrogen atom attached thereto are optionally joined to form a substituted or unsubstituted heterocycloalkyl;

[0181] each Ra is independently a substituted or unsubstituted C1-C6 alkyl; and

[0182] Rb is hydrogen, deuterium, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, or a substituted or unsubstituted C3-C10 cycloalkyl.

[0183] (102) The compound of (101), which is selected from the group consisting ofor a pharmaceutically acceptable salt, solvate, or prodrug thereof.(103) A pharmaceutical composition, comprising the compound of (101) or (102) and a pharmaceutically acceptable excipient.(104) A method of treating a subject with a disease or disorder associated with a serotonin 5-HT2 receptor, the method comprising:administering to the subject a therapeutically effective amount of the compound of (101) or (102).

[0187] (105) Use of a compound of any one of (1) to (20) for treating a subject with a disease or disorder, including a disease or disorder associated with a serotonin 5-HT2 receptor.

[0188] (106) Use of a compound of (97) or (98) for treating a subject with a disease or disorder, including a disease or disorder associated with a serotonin 5-HT2 receptor.

[0189] (107) Use of a compound of (101) or (102) for treating a subject with a disease or disorder, including a disease or disorder associated with a serotonin 5-HT2 receptor.BRIEF DESCRIPTION OF THE DRAWINGS

[0190] The forgoing paragraphs have been provided by way of general introduction and are not intended to limit the scope of the following claims. The described embodiments, together with further advantages, will be best understood by reference to the following detailed description when considered in conjunction with the accompanying drawings, wherein:

[0191] FIG. 1 illustrates the synthetic route for making compound II-1;

[0192] FIG. 2 illustrates the synthetic route for making compound II-2;

[0193] FIG. 3 illustrates the synthetic route for making compound II-3;

[0194] FIG. 4 illustrates the synthetic route for making compound II-4;

[0195] FIG. 5 illustrates the synthetic route for making compound II-14;

[0196] FIG. 6 illustrates the synthetic route for making compound III-1;

[0197] FIG. 7 illustrates the synthetic route for making compound III-2;

[0198] FIG. 8 illustrates the synthetic route for making compound IV-1;

[0199] FIG. 9 illustrates the synthetic route for making compound IV-2;

[0200] FIG. 10 illustrates the synthetic route for making compound IV-3;

[0201] FIG. 11 illustrates the synthetic route for making compound IV-5;

[0202] FIG. 12 illustrates the synthetic route for making compound IV-12;

[0203] FIG. 13 illustrates the synthetic route for making compound I-1;

[0204] FIG. 14 illustrates the synthetic route for making compound I-2;

[0205] FIG. 15 illustrates the synthetic route for making compound I-3;

[0206] FIG. 16 illustrates the synthetic route for making compound I-4;

[0207] FIG. 17 illustrates the synthetic route for making compound I-5;

[0208] FIG. 18 illustrates the synthetic route for making compound I-6;

[0209] FIG. 19 illustrates the synthetic route for making compound I-7;

[0210] FIG. 20 illustrates the synthetic route for making compounds of Formula (I) with a fluoropropoxy or fluorothiopropoxy substituent as R4, e.g., compounds II-16, II-17, II-18, II-19, II-20 and II-21;

[0211] FIG. 21 illustrates the synthetic route for making compound I-8;

[0212] FIG. 22 illustrates the synthetic route for making compound I-10;

[0213] FIG. 23 illustrates the synthetic route for making compound I-11;

[0214] FIG. 24 illustrates the synthetic route for making compound I-13;

[0215] FIG. 25 illustrates the synthetic route for making compound II-10;

[0216] FIG. 26 illustrates the synthetic route for making compound II-23;

[0217] FIG. 27 illustrates the synthetic route for making compound V-1;

[0218] FIG. 28 illustrates the synthetic route for making compound VI-1;

[0219] FIG. 29 illustrates the synthetic route for making compound IV-33;

[0220] FIG. 30 illustrates the synthetic route for making Reference Compound 1;

[0221] FIG. 31 is a graph showing agonist-labeled 5-HT2A radioligand ([3H]ketanserin) competition binding using compound II-1 and IV-1; at least three independent experiments, with compounds tested in duplicate were performed with data shown being the average results from all experiments combined; Kd for [3H]ketanserin was set to 1.57 nM, and data were analyzed using a one-site, fit Ki model (GraphPad Prism 9); the data point for −10 samples is total, specific binding (no compound present) and −4 was interpolated to complete the binding curves to 0 specific binding;

[0222] FIG. 32 is a graph showing agonist-labeled 5-HT2A radioligand ([3H]ketanserin) competition binding using compound II-23 and IV-3; at least three independent experiments, with compounds tested in duplicate were performed with data shown being the average results from all experiments combined; Kd for [3H]ketanserin was set to 1.57 nM, and data were analyzed using a one-site, fit Ki model (GraphPad Prism 9); the data point for −10 samples is total, specific binding (no compound present) and −4 was interpolated to complete the binding curves to 0 specific binding;

[0223] FIG. 33 is a graph showing agonist-labeled 5-HT2A radioligand ([3H]ketanserin) competition binding using compound I-1 and II-10 and 5-HT as positive control; data shown are the average results from 2-6 experiments combined (N=6-12 replicates per concentration); Kd for [3H]ketanserin was set to 1.57 nM, and data were analyzed using a two-site, fit Ki model (GraphPad Prism 9); the data point for −10 samples is total, specific binding (no compound present) and −4 was interpolated to complete the binding curves to 0 specific binding;

[0224] FIG. 34 is a graph showing agonist-labeled 5-HT2A radioligand ([3H]LSD) competition binding using compounds I-13 and II-4; three independent experiments with compounds tested in duplicate (5-HT, control) or triplicate (I-13, II-4) were performed with data shown being the average results from all experiments combined (N=6-12 replicates per concentration); Kd for [3H]LSD was set to 0.78 nM, and data were analyzed using a one-site, fit Ki model (GraphPad Prism 9); the data point for −10 samples is total, specific binding (no compound present) and −4 was interpolated to complete the binding curves to 0 specific binding;

[0225] FIG. 35 is a graph showing agonist-labeled 5-HT2A radioligand ([3H]LSD) competition binding using compounds VI-1, II-3, and III-2; up to 11 independent experiments with 5-HT tested in duplicate and compounds II-3, III-2, VI-1 in triplicate were performed with data shown being the average results from all experiments combined (N=up to 33 replicates); Kd for [3H]LSD was set to 0.78 nM, and data were analyzed using a one-site, fit Ki model (GraphPad Prism 9); the data point for −10 samples is total, specific binding (no compound present) and −4 was interpolated to complete the binding curves to 0 specific binding;

[0226] FIG. 36 is a graph showing agonist-labeled 5-HT2A radioligand ([3H]LSD) competition binding using compounds I-4 and I-7; four independent experiments with 5-HT tested in duplicate (N=8 replicates) and compounds I-4 and I-7 in triplicate (N=12) were performed with data shown being the average results from all experiments combined; Kd for [3H]LSD was set to 0.78 nM, and data were analyzed using a one-site, fit Ki model (GraphPad Prism 9); the data point for −10 samples is total, specific binding (no compound present) and −4 was interpolated to complete the binding curves to 0 specific binding;

[0227] FIG. 37 is a graph showing agonist-labeled 5-HT2A radioligand ([3H]LSD) competition binding using compound I-3; four independent experiments with 5-HT tested in duplicate (N=8 replicates) and compound I-3 in triplicate (N=12) were performed with data shown being the average results from all experiments combined; Kd for [3H]LSD was set to 0.78 nM, and data were analyzed using a one-site, fit Ki model (GraphPad Prism 9); the data point for −10 samples is total, specific binding (no compound present) and −4 was interpolated to complete the binding curves to 0 specific binding;

[0228] FIG. 38 is a graph showing agonist-labeled 5-HT2A radioligand ([3H]LSD) competition binding using compound I-2; four independent experiments with 5-HT tested in duplicate (N=8 replicates) and compound I-2 in triplicate (N=12) were performed with data shown being the average results from all experiments combined; Kd for [3H]LSD was set to 0.78 nM, and data were analyzed using a one-site, fit Ki model (GraphPad Prism 9); the data point for −10 samples is total, specific binding (no compound present) and −4 was interpolated to complete the binding curves to 0 specific binding;

[0229] FIG. 39 is a graph showing agonist-labeled 5-HT2A radioligand ([3H]LSD) competition binding using compounds I-5 and I-6; seven independent experiments with 5-HT tested in duplicate (N=14 replicates) and compounds I-5 and I-6 in triplicate (N=21) were performed with data shown being the average results from all experiments combined; Kd for [3H]LSD was set to 0.78 nM, and data were analyzed using a one-site, fit Ki model (GraphPad Prism 9); the data point for −10 samples is total, specific binding (no compound present) and −4 was interpolated to complete the binding curves to 0 specific binding;

[0230] FIG. 40 is a graph showing agonist-labeled 5-HT2A radioligand ([3H]LSD) competition binding using compound I-8; three independent experiments with 5-HT tested in duplicate (N=6 replicates) and compound I-8 in triplicate (N=9) were performed with data shown being the average results from all experiments combined; Kd for [3H]LSD was set to 0.78 nM, and data were analyzed using a one-site, fit Ki model (GraphPad Prism 9) the data point for −10 samples is total, specific binding (no compound present) and −4 was interpolated to complete the binding curves to 0 specific binding;

[0231] FIG. 41 is a graph showing agonist-labeled 5-HT2A radioligand ([3H]LSD) competition binding using compound V-1; two independent experiments with 5-HT tested in duplicate (N=4 replicates) and compound V-1 in triplicate (N=6) were performed with data shown being the average results from all experiments combined; Kd for [3H]LSD was set to 0.78 nM, and data were analyzed using a one-site, fit Ki model (GraphPad Prism 9); the data point for −10 samples is total, specific binding (no compound present) and −4 was interpolated to complete the binding curves to 0 specific binding;

[0232] FIG. 42 is a graph showing a dose-response of 5-HT2A functional assay as a percent of control agonist response (5-HT); compound I-1 was tested in duplicate at the indicated concentrations and the EC50 and Emax values were determined by non-linear regression analysis of the concentration-response curves generated with the mean replicate values using Hill equation curve fitting;

[0233] FIG. 43 is a graph showing a dose-response of 5-HT2A functional assay as a percent of control agonist response (5-HT); compounds I-3, I-8, and VI-1 were tested in duplicate at the indicated concentrations and the EC50 and Emax values were determined by non-linear regression analysis of the concentration-response curves generated with the mean replicate values using Hill equation curve fitting;

[0234] FIG. 44 is a graph showing a dose-response of 5-HT2A functional assay as a percent of control agonist response (5-HT); compound I-10 was tested in duplicate at the indicated concentrations and the EC50 and Emax values were determined by non-linear regression analysis of the concentration-response curves generated with the mean replicate values using Hill equation curve fitting;

[0235] FIG. 45 is a graph showing a dose-response of 5-HT2A functional assay as a percent of control agonist response (5-HT); compound V-1 was tested in duplicate at the indicated concentrations and the EC50 and Emax values were determined by non-linear regression analysis of the concentration-response curves generated with the mean replicate values using Hill equation curve fitting;

[0236] FIG. 46 is a graph showing a dose-response of 5-HT2A functional assay (TRUPATH) as a percent of control agonist response (5-HT); compound V-1 was tested in 11 replicates at the indicated concentrations and the EC50 and Emax values were determined by non-linear regression analysis of the concentration-response curves generated with the mean replicate values using Hill equation curve fitting;

[0237] FIG. 47 is a graph showing a dose-response of 5-HT2B functional assay as a percent of control agonist response (5-HT); compound I-1 was tested in duplicate at the indicated concentrations and the EC50 and Emax values were determined by non-linear regression analysis of the concentration-response curves generated with the mean replicate values using Hill equation curve fitting;

[0238] FIG. 48 is a graph showing a dose-response of 5-HT2B functional assay as a percent of control agonist response (5-HT); compounds I-3, I-8, and VI-1 were tested in duplicate at the indicated concentrations and the EC50 and Emax values were determined by non-linear regression analysis of the concentration-response curves generated with the mean replicate values using Hill equation curve fitting;

[0239] FIG. 49 is a graph showing a dose-response of 5-HT2B functional assay as a percent of control agonist response (5-HT); compound I-10 was tested in duplicate at the indicated concentrations and the EC50 and Emax values were determined by non-linear regression analysis of the concentration-response curves generated with the mean replicate values using Hill equation curve fitting;

[0240] FIG. 50 is a graph showing a dose-response of 5-HT2B functional assay as a percent of control agonist response (5-HT); compound V-1 was tested in duplicate at the indicated concentrations and the EC50 and Emax values were determined by non-linear regression analysis of the concentration-response curves generated with the mean replicate values using Hill equation curve fitting;

[0241] FIG. 51 is a graph showing a dose-response of 5-HT2C functional assay (TRUPATH) as a percent of control agonist response (5-HT); compound V-1 was tested in 9 replicates at the indicated concentrations and the EC50 and Emax values were determined by non-linear regression analysis of the concentration-response curves generated with the mean replicate values using Hill equation curve fitting;

[0242] FIG. 52 is a graph showing the head-twitch response in adult, male C57BL / 6J mice after administration of 0.1, 0.3, 1, and 3 mg / kg s.c. of compound I-1 and observed at the indicated time points; DOI was used as a positive control, vehicle as a negative control;

[0243] FIGS. 53A-53B are graphs showing oral administration of I-1 (1-10 mg / kg, p.o.) induced the HTR in C57BL / 6 mice; I-1 at doses of 1, 3 and 10 mg / kg p.o. produced a dose-dependent increase in HTRs similar to I-1 3 mg / kg s.c. (n=10 per group) and DOI 1 mg / kg i.p. (n=4); the HTR is compared to saline vehicle (n=4) across minutes 1-30 (FIG. 53A) and 120-150 (FIG. 53B) post-dosing, showing that significant numbers of head-twitches were present in all test compound groups in minutes 1-30, and minutes 120-150; *p<0.05; **p<0.01 vs. vehicle;

[0244] FIGS. 54A-54B are graphs showing mean I-1 concentrations ±SD in mouse plasma and brain samples over time in C57BL / 6J mice (n=3) administered orally (FIG. 54A) or subcutaneously (FIG. 54B) at 3 mg / kg and plasma and brain samples were collected at the indicated time points;

[0245] FIGS. 55A-55B are graphs showing the mean concentrations ±SD of I-1 in rat plasma samples and brain samples over time on a linear scale after intravenous administration at 1 mg / kg (FIG. 55A) and oral administration at 5 mg / kg (FIG. 55B) to male Wistar rats (n=3);

[0246] FIGS. 56A-56B are graphs showing the mean concentrations ±SD of I-1 in rat plasma, brain, and CSF samples over time on a linear scale (FIG. 56A) and a log scale (FIG. 56B) after intravenous administration (1 mg / kg, s.c.) to male Sprague-Dawley rats (n=4 per time point); and

[0247] FIGS. 57A-57J are graphs showing transcriptional changes in the frontal cortex of male C57BL / 6J mice in the acute phase (2 h) after treatment with treatment groups A, B, C, and D in the following brain markers of neuroplasticity: bdnf (FIG. 57A), psd-95 (FIG. 57B), homer1 (FIG. 57C), Egr2 (FIG. 57D), cFos (FIG. 57E), mTOR (FIG. 57F), Creb1 (FIG. 57G), Syn1 (FIG. 57H), Nptn (FIG. 57I), and Igf1 (FIG. 57J); statistical analysis by one-way ANOVA followed by multiple comparisons against vehicle group on log transformed data, back transformed data presented, *=p<0.05, **=p<0.01, ****=p<0.001.DETAILED DESCRIPTION

[0248] In the following detailed description of the embodiments of the instant disclosure, numerous specific details are set forth in order to provide a thorough understanding of the disclosed embodiments. However, it will be obvious to one skilled in the art that the embodiments of this disclosure may be practiced without these specific details. In other instances, well known methods, procedures, components, and circuits have not been described in detail so as not to unnecessarily obscure aspects of the embodiments of the instant disclosure.Definitions

[0249] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs.

[0250] “Alkyl” refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and such as 1 to 6 carbon atoms, or 1 to 5, or 1 to 4, or 1 to 3, or 1 to 2 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3—), ethyl (CH3CH2—), n-propyl (CH3CH2CH2—), isopropyl ((CH3)2CH—), n-butyl (CH3CH2CH2CH2—), isobutyl ((CH3)2CHCH2—), sec-butyl ((CH3)(CH3CH2)CH—), t-butyl (t-Bu)((CH3)3C—), n-pentyl (CH3CH2CH2CH2CH2—), and neopentyl ((CH3)3CCH2—).

[0251] The term “substituted alkyl” refers to an alkyl group as defined herein wherein one or more carbon atoms in the alkyl chain have been optionally replaced with a heteroatom such as —O—, —N—, −S—, —S(O)n— (where n is 0 to 2), —NR— (where R is hydrogen or alkyl) and having from 1 to 10 substituents selected from the group consisting of deuterium, alkoxy, substituted alkoxy, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO2-alkyl, —SO2-aryl, —SO2-heteroaryl, and —NR′R″, wherein R′ and R″ may be the same or different and are chosen from hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic.

[0252] “Alkylene” refers to divalent aliphatic hydrocarbyl groups having from 1 to 6, including, for example, 1 to 3 carbon atoms that are either straight-chained or branched, and which are optionally interrupted with one or more groups selected from —O—, —NR10—, —NR10C(O)—, —C(O)NR10— and the like. This term includes, by way of example, methylene (—CH2—), ethylene (—CH2CH2—), n-propylene (—CH2CH2CH2—), iso-propylene (—CH2CH(CH3)—), (—C(CH3)2CH2CH2—), (—C(CH3)2CH2C(O)—), (—C(CH3)2CH2C(O)NH—), (—CH(CH3)CH2—), and the like.

[0253] “Substituted alkylene” refers to an alkylene group having from 1 to 3 hydrogens replaced with substituents as described for carbons in the definition of “substituted” below.

[0254] The term “alkane” refers to alkyl group and alkylene group, as defined herein.

[0255] The term “alkylaminoalkyl”, “alkylaminoalkenyl” and “alkylaminoalkynyl” refers to the groups R′NHR″— where R′ is alkyl group as defined herein and R″ is alkylene, alkenylene or alkynylene group as defined herein.

[0256] The term “alkaryl” or “aralkyl” refers to the groups -alkylene-aryl and -substituted alkylene-aryl where alkylene, substituted alkylene and aryl are defined herein.

[0257] “Alkoxy” refers to the group —O-alkyl, wherein alkyl is as defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, and the like. The term “alkoxy” also refers to the groups alkenyl-O—, cycloalkyl-O—, cycloalkenyl-O—, and alkynyl-O—, where alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are as defined herein.

[0258] The term “substituted alkoxy” refers to the groups substituted alkyl-O—, substituted alkenyl-O—, substituted cycloalkyl-O—, substituted cycloalkenyl-O—, and substituted alkynyl-O— where substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl and substituted alkynyl are as defined herein.

[0259] The term “alkoxyamino” refers to the group —NH-alkoxy, wherein alkoxy is defined herein.

[0260] The term “haloalkoxy” refers to the groups alkyl-O— wherein one or more hydrogen atoms on the alkyl group have been substituted with a halo group and include, by way of examples, groups such as trifluoromethoxy, and the like.

[0261] The term “haloalkyl” refers to a substituted alkyl group as described above, wherein one or more hydrogen atoms on the alkyl group have been substituted with a halo group. Examples of such groups include, without limitation, fluoroalkyl groups, such as trifluoromethyl, difluoromethyl, trifluoroethyl and the like.

[0262] The term “alkylalkoxy” refers to the groups -alkylene-O-alkyl, alkylene-O-substituted alkyl, substituted alkylene-O-alkyl, and substituted alkylene-O-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein.

[0263] The term “alkylthioalkoxy” refers to the group -alkylene-S-alkyl, alkylene-S-substituted alkyl, substituted alkylene-S-alkyl and substituted alkylene-S-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein.

[0264] “Alkenyl” refers to straight chain or branched hydrocarbyl groups having from 2 to 6 carbon atoms, for example 2 to 4 carbon atoms and having at least 1, for example from 1 to 2 sites of double bond unsaturation. This term includes, by way of example, bi-vinyl, allyl, and but-3-en-1-yl. Included within this term are the cis and trans isomers or mixtures of these isomers.

[0265] The term “substituted alkenyl” refers to an alkenyl group as defined herein having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO2-alkyl, —SO2-substituted alkyl, —SO2-aryl and —SO2-heteroaryl.

[0266] “Alkynyl” refers to straight or branched monovalent hydrocarbyl groups having from 2 to 10 carbon atoms, for example, 2 to 3 carbon atoms, 3 to 6 carbon atoms, and having at least 1 and for example, from 1 to 2 sites of triple bond unsaturation. Examples of such alkynyl groups include acetylenyl (—C≡CH), and propargyl (—CH2C≡CH).

[0267] The term “substituted alkynyl” refers to an alkynyl group as defined herein having from 1 to 5 substituents, or from 1 to 3 substituents, selected from deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO2-alkyl, —SO2-substituted alkyl, —SO2-aryl, and —SO2-heteroaryl.

[0268] “Alkynyloxy” refers to the group —O-alkynyl, wherein alkynyl is as defined herein. Alkynyloxy includes, by way of example, ethynyloxy, propynyloxy, and the like.

[0269] “Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substituted alkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—, substituted alkynyl-C(O)—, cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—, cycloalkenyl-C(O)—, substituted cycloalkenyl-C(O)—, aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—, substituted heteroaryl-C(O)—, heterocyclyl-C(O)—, and substituted heterocyclyl-C(O)—, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. For example, acyl includes the “acetyl” group CH3C(O)

[0270] “Acylamino” refers to the groups —NR20C(O)alkyl, —NR20C(O)substituted alkyl, —NR20C(O)cycloalkyl, —NR20C(O)substituted cycloalkyl, —NR20C(O)cycloalkenyl, —NR20C(O)substituted cycloalkenyl, —NR20C(O)alkenyl, —NR20C(O)substituted alkenyl, —NR20C(O)alkynyl, —NR20C(O)substituted alkynyl, —NR20C(O)aryl, —NR20C(O)substituted aryl, —NR20C(O)heteroaryl, —NR20C(O)substituted heteroaryl, —NR20C(O)heterocyclic, and —NR20C(O)substituted heterocyclic, wherein R20 is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0271] “Aminocarbonyl” or the term “aminoacyl” refers to the group —C(O)NR21R22, wherein R21 and R22 independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R21 and R22 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0272] “Aminocarbonylamino” refers to the group —NR21C(O)NR22R23 where R21, R22, and R23 are independently selected from hydrogen, alkyl, aryl or cycloalkyl, or where two R groups are joined to form a heterocyclyl group.

[0273] The term “alkoxycarbonylamino” refers to the group —NRC(O)OR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclyl wherein alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.

[0274] The term “acyloxy” refers to the groups alkyl-C(O)O—, substituted alkyl-C(O)O—, cycloalkyl-C(O)O—, substituted cycloalkyl-C(O)O—, aryl-C(O)O—, heteroaryl-C(O)O—, and heterocyclyl-C(O)O— wherein alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.

[0275] “Aminosulfonyl” refers to the group —SO2NR21R22, wherein R21 and R22 independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where R21 and R22 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0276] “Sulfonylamino” refers to the group —NR21SO2R22, wherein R21 and R22 independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R21 and R22 are optionally joined together with the atoms bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0277] “Aryl” or “Ar” refers to a monovalent aromatic carbocyclic group of from 6 to 18 carbon atoms having a single ring (such as is present in a phenyl group) or a ring system having multiple condensed rings (examples of such aromatic ring systems include naphthyl, anthryl and indanyl) which condensed rings may or may not be aromatic, provided that the point of attachment is through an atom of an aromatic ring. This term includes, by way of example, phenyl and naphthyl. Unless otherwise constrained by the definition for the aryl substituent, such aryl groups can optionally be substituted with from 1 to 5 substituents, or from 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO— heteroaryl, —SO2-alkyl, —SO2-substituted alkyl, —SO2-aryl, —SO2-heteroaryl and trihalomethyl.

[0278] “Aryloxy” refers to the group —O-aryl, wherein aryl is as defined herein, including, by way of example, phenoxy, naphthoxy, and the like, including optionally substituted aryl groups as also defined herein.

[0279] “Amino” refers to the group —NH2.

[0280] The term “substituted amino” refers to the group —NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, and heterocyclyl provided that at least one R is not hydrogen.

[0281] The term “azido” refers to the group —N3.

[0282] “Carboxyl,”“carboxy” or “carboxylate” refers to —CO2H or salts thereof.

[0283] “Carboxyl ester” or “carboxy ester” or the terms “carboxyalkyl” or “carboxylalkyl” refers to the groups —C(O)O-alkyl, —C(O)O-substituted alkyl, —C(O)O-alkenyl, —C(O)O-substituted alkenyl, —C(O)O-alkynyl, —C(O)O-substituted alkynyl, —C(O)O-aryl, —C(O)O-substituted aryl, —C(O)O-cycloalkyl, —C(O)O-substituted cycloalkyl, —C(O)O-cycloalkenyl, —C(O)O-substituted cycloalkenyl, —C(O)O-heteroaryl, —C(O)O-substituted heteroaryl, —C(O)O-heterocyclic, and —C(O)O-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0284] “(Carboxyl ester)oxy” or “carbonate” refers to the groups —O—C(O)O-alkyl, —O—C(O)O-substituted alkyl, —O—C(O)O-alkenyl, —O—C(O)O-substituted alkenyl, —O—C(O)O-alkynyl, —O—C(O)O-substituted alkynyl, —O—C(O)O-aryl, —O—C(O)O-substituted aryl, —O—C(O)O-cycloalkyl, —O—C(O)O-substituted cycloalkyl, —O—C(O)O-cycloalkenyl, —O—C(O)O-substituted cycloalkenyl, —O—C(O)O-heteroaryl, —O—C(O)O-substituted heteroaryl, —O—C(O)O-heterocyclic, and —O—C(O)O-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0285] “Cyano” or “nitrile” refers to the group —CN.

[0286] “Cycloalkyl” refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including fused, bridged, and spiro ring systems. Examples of suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and the like. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.

[0287] The term “substituted cycloalkyl” refers to cycloalkyl groups having from 1 to 5 substituents, or from 1 to 3 substituents, selected from deuterium, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO2-alkyl, —SO2-substituted alkyl, —SO2-aryl and —SO2—heteroaryl.

[0288] “Cycloalkenyl” refers to non-aromatic cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple rings and having at least one double bond and for example, from 1 to 2 double bonds.

[0289] The term “substituted cycloalkenyl” refers to cycloalkenyl groups having from 1 to 5 substituents, or from 1 to 3 substituents, selected from deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO2—alkyl, —SO2-substituted alkyl, —SO2-aryl and —SO2-heteroaryl.

[0290] “Cycloalkynyl” refers to non-aromatic cycloalkyl groups of from 5 to 10 carbon atoms having single or multiple rings and having at least one triple bond.

[0291] “Cycloalkoxy” refers to —O-cycloalkyl.

[0292] “Cycloalkenyloxy” refers to —O-cycloalkenyl.

[0293] “Halo” or “halogen” refers to fluoro, chloro, bromo, and iodo.

[0294] “Hydroxy” or “hydroxyl” refers to the group —OH.

[0295] “Heteroaryl” refers to an aromatic group of from 1 to 15 carbon atoms, such as from 1 to 10 carbon atoms and 1 to 10 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. Such heteroaryl groups can have a single ring (such as, pyridinyl, imidazolyl or furyl) or multiple condensed rings in a ring system (for example as in groups such as, indolizinyl, quinolinyl, benzofuran, benzimidazolyl or benzothienyl), wherein at least one ring within the ring system is aromatic and at least one ring within the ring system is aromatic, provided that the point of attachment is through an atom of an aromatic ring. In some embodiments, the nitrogen and / or sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N→O), sulfinyl, or sulfonyl moieties. This term includes, by way of example, pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl. Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with 1 to 5 substituents, or from 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, —SO—alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO2-alkyl, —SO2-substituted alkyl, —SO2-aryl and —SO2—heteroaryl, and trihalomethyl.

[0296] The term “heteroaralkyl” refers to the groups -alkylene-heteroaryl where alkylene and heteroaryl are defined herein. This term includes, by way of example, pyridylmethyl, pyridylethyl, indolylmethyl, and the like.

[0297] “Heteroaryloxy” refers to —O-heteroaryl.

[0298] “Heterocycle,”“heterocyclic,”“heterocycloalkyl,” and “heterocyclyl” refer to a saturated or unsaturated group having a single ring or multiple condensed rings, including fused bridged and spiro ring systems, and having from 3 to 20 ring atoms, including 1 to 10 hetero atoms. These ring atoms are selected from the group consisting of nitrogen, sulfur, or oxygen, wherein, in fused ring systems, one or more of the rings can be cycloalkyl, aryl, or heteroaryl, provided that the point of attachment is through the non-aromatic ring. In some embodiments, the nitrogen and / or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, —S(O)—, or —SO2— moieties.

[0299] Examples of heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to as thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine, tetrahydrofuranyl, benzo[d][1,3]oxathiole, benzo[d][1,3]dioxole, and the like.

[0300] Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to 5, or from 1 to 3 substituents, selected from deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO2-alkyl, —SO2-substituted alkyl, —SO2-aryl, —SO2-heteroaryl, and fused heterocycle.

[0301] “Heterocyclyloxy” refers to the group —O-heterocyclyl.

[0302] The term “heterocyclylthio” refers to the group heterocyclic-S—.

[0303] The term “heterocyclene” refers to the diradical group formed from a heterocycle, as defined herein.

[0304] The term “hydroxyamino” refers to the group —NHOH.

[0305] “Nitro” refers to the group —NO2.

[0306] “Oxo” refers to the atom (═O).

[0307] “Sulfonyl” refers to the group SO2-alkyl, SO2-substituted alkyl, SO2-alkenyl, SO2-substituted alkenyl, SO2-cycloalkyl, SO2-substituted cycloalkyl, SO2-cycloalkenyl, SO2-substituted cylcoalkenyl, SO2-aryl, SO2-substituted aryl, SO2-heteroaryl, SO2-substituted heteroaryl, SO2-heterocyclic, and SO2-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Sulfonyl includes, by way of example, methyl-SO2—, phenyl-SO2—, and 4-methylphenyl-SO2—.

[0308] “Sulfonyloxy” refers to the group —OSO2-alkyl, —OSO2-substituted alkyl, —OSO2-alkenyl, —OSO2-substituted alkenyl, —OSO2-cycloalkyl, —OSO2-substituted cycloalkyl, —OSO2-cycloalkenyl, —OSO2-substituted cylcoalkenyl, —OSO2-aryl, —OSO2-substituted aryl, —OSO2-heteroaryl, —OSO2-substituted heteroaryl, —OSO2-heterocyclic, and —OSO2-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0309] The term “aminocarbonyloxy” refers to the group —OC(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.

[0310] “Thiol” refers to the group —SH.

[0311] “Thioxo” or the term “thioketo” refers to the atom (═S).

[0312] “Alkylthio” or the term “thioalkoxy” refers to the group —S-alkyl, wherein alkyl is as defined herein. In some embodiments, sulfur may be oxidized to —S(O)—. The sulfoxide may exist as one or more stereoisomers.

[0313] The term “substituted thioalkoxy” refers to the group —S-substituted alkyl.

[0314] The term “thioaryloxy” refers to the group aryl-S— wherein the aryl group is as defined herein including optionally substituted aryl groups also defined herein.

[0315] The term “thioheteroaryloxy” refers to the group heteroaryl-S— wherein the heteroaryl group is as defined herein including optionally substituted aryl groups as also defined herein.

[0316] The term “thioheterocyclooxy” refers to the group heterocyclyl-S— wherein the heterocyclyl group is as defined herein including optionally substituted heterocyclyl groups as also defined herein.

[0317] In addition to the disclosure herein, the term “substituted,” when used to modify a specified group or radical, can also mean that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituent groups as defined below.

[0318] In addition to the groups disclosed with respect to the individual terms herein, substituent groups for substituting for one or more hydrogens (any two hydrogens on a single carbon can be replaced with ═O, ═NR70, ═N—OR70, ═N2 or ═S) on saturated carbon atoms in the specified group or radical are, unless otherwise specified, deuterium, —R60, halo, ═O, —OR70, —SR70, —NR80R80, trihalomethyl, —CN, —OCN, —SCN, —NO, —NO2, ═N2, —N3, —SO2R70, —SO2O−M+, —SO2OR70, —OSO2R70, —OSO2O−M+, —OSO2OR70, —P(O)(O—)2(M+)2, —P(O)(OR70)O−M+, —P(O)(OR70)2, —C(O)R70, —C(S)R70, —C(NR70)R70, —C(O)O−M+, —C(O)OR70, —C(S)OR70, —C(O)NR80R80, —C(NR70)NR80R80, —OC(O)R70, —OC(S)R70, —OC(O)O−M+, —OC(O)OR70, —OC(S)OR70, —NR70C(O)R70, —NR70C(S)R70, —NR70CO2−M+, —NR70CO2R70, —NR70C(S)OR70, —NR70C(O)NR80R80, —NR70C(NR70)R70 and —NR70C(NR70)NR80R80, where R60 is selected from the group consisting of optionally substituted alkyl, cycloalkyl, heteroalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, each R70 is independently hydrogen or R60; each R80 is independently R70 or alternatively, two R80's, taken together with the nitrogen atom to which they are bonded, form a 5-, 6- or 7-membered heterocycloalkyl which may optionally include from 1 to 4 of the same or different additional heteroatoms selected from the group consisting of O, N and S, of which N may have —H or C1-C3 alkyl substitution; and each M+ is a counter ion with a net single positive charge. Each M+ may independently be, for example, an alkali ion, such as K+, Na+, Li+; an ammonium ion, such as +N(R60)4; or an alkaline earth ion, such as [Ca2+]0.5, [Mg2+]0.5, or [Ba2+]0.5 (“subscript 0.5 means that one of the counter ions for such divalent alkali earth ions can be an ionized form of a compound of the disclosure and the other a typical counter ion such as chloride, or two ionized compounds disclosed herein can serve as counter ions for such divalent alkali earth ions, or a doubly ionized compound of the disclosure can serve as the counter ion for such divalent alkali earth ions). As specific examples, —NR80R80 is meant to include —NH2, —NH-alkyl, N-pyrrolidinyl, N-piperazinyl, 4N-methyl-piperazin-1-yl and N-morpholinyl.

[0319] In addition to the disclosure herein, substituent groups for hydrogens on unsaturated carbon atoms in “substituted” alkene, alkyne, aryl and heteroaryl groups are, unless otherwise specified, deuterium, —R60, halo, —O−M+, —OR70, —SR70, —S−M+, —NR80R80, trihalomethyl, —CF3, —CN, —OCN, —SCN, —NO, —NO2, —N3, —SO2R70, —SO3−M+, —SO3R70, —OSO2R70, —OSO3−M+, —OSO3R70, —PO3−2(M+)2, —P(O)(OR70)O−M+, —P(O)(OR70)2, —C(O)R70, —C(S)R70, —C(NR70)R70, —CO2−M+, —CO2R70, —C(S)OR70, —C(O)NR8OR80, —C(NR70)NR8OR80, —OC(O)R70, —OC(S)R70, —OCO2−M+, —OCO2R70, —OC(S)OR70, —NR70C(O)R70, —NR70C(S)R70, —NR70CO2−M+, —NR70CO2R70, —NR70C(S)OR70, —NR70C(O)NR8OR80, —NR70C(NR70)R70 and —NR70C(NR70)NR80R80, where R60, R70, R80 and M+ are as previously defined, provided that in case of substituted alkene or alkyne, the substituents are not —O−M+, —OR70, —SR70, or —S−M+.

[0320] In addition to the groups disclosed with respect to the individual terms herein, substituent groups for hydrogens on nitrogen atoms in “substituted” heteroalkyl and cycloheteroalkyl groups are, unless otherwise specified, —R60, —O−M+, —OR70, —SR70, —S−M+, —NR80R80, trihalomethyl, —CF3, —CN, —NO, —NO2, —S(O)2R70, —S(O)2O−M+, —S(O)2OR70, —OS(O)2R70, —OS(O)2O−M+, —OS(O)2OR70, —P(O)(O—)2(M+)2, —P(O)(OR70)O−M+, —P(O)(OR70)(OR70), —C(O)R70, —C(S)R70, —C(NR70)R70, —C(O)OR70, —C(S)OR70, —C(O)NR80R80, —C(NR70)NR80R80, —OC(O)R70, —OC(S)R70, —OC(O)OR70, —OC(S)OR70, —NR70C(O)R70, —NR70C(S)R70, —NR70C(O)OR70, —NR70C(S)OR70, —NR70C(O)NR8OR80, —NR70C(NR70)R70 and —NR70C(NR70)NR80R80, where R60, R70, R80 and M+ are as previously defined.

[0321] In addition to the disclosure herein, in a certain embodiment, a group that is substituted has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent.

[0322] It is understood that in all substituted groups defined above, polymers arrived at by defining substituents with further substituents to themselves (e.g., substituted aryl having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group, which is further substituted by a substituted aryl group, etc.) are not intended for inclusion herein, unless specified otherwise. In such cases, the maximum number of such substitutions is three. For example, serial substitutions of substituted aryl groups specifically contemplated herein are limited to substituted aryl-(substituted aryl)-substituted aryl. However, substituent groups defined as e.g., polyethers may contain serial substitution greater than three, e.g., —O—(CH2CH2O)n—H, where n can be 1, 2, 3, or greater.

[0323] Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent “arylalkyloxycarbonyl” refers to the group (aryl)-(alkyl)-O—C(O)—.

[0324] As to any of the groups disclosed herein which contain one or more substituents, it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and / or synthetically non-feasible. In addition, the subject compounds include all stereochemical isomers arising from the substitution of these compounds.

[0325] As used herein, the term “fatty” describes a compound with a long-chain (linear) hydrophobic portion made up of hydrogen and anywhere from 4 to 26 carbon atoms, which may be fully saturated or partially unsaturated.

[0326] When it is defined that a substituent or group “comprise(s) deuterium” or is “comprising deuterium,” it is to be understood that the substituent or group may itself be deuterium, or the substituent or group may contain at least one deuterium substitution in its chemical structure. For example, when substituent “—R” is defined to comprise deuterium, it is to be understood that —R may be -D (-deuterium), or a group such as —CD3 that is consistent with the other requirements set forth of —R.

[0327] The phrases “pharmaceutically acceptable,”“physiologically acceptable,” and the like, are employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. When referencing salts, the phrases “pharmaceutically acceptable salt,”“physiologically acceptable salt,” and the like, means a salt which is acceptable for administration to a patient, such as a mammal (salts with counterions having acceptable mammalian safety for a given dosage regime). As is well known in the art, such salts can be derived from pharmaceutically acceptable inorganic or organic bases, by way of example, sodium, potassium, calcium, magnesium, lithium, aluminum, zinc, and ammonium and tetraalkylammonium salts (e.g., salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines, hydroxyalkylamines, lysine, arginine, N-methylglucamine, procaine, etc.), and the like, and when the molecule contains a basic functionality, addition salts with inorganic acids, such as hydrochloride, hydrobromide, sulfate, sulfamate, phosphate, nitrate, perchlorate salts, and the like, and addition salts with organic acids, such as formate, tartrate, besylate, mesylate, acetate, maleate, malonate, oxalate, fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemi-oxalate, hemi-fumarate, propionate, stearate, lactate, citrate, ascorbate, pamoate, hydroxymaleate, phenylacetate, glutamate, 2-acetoxybenzoate, tosylate, ethanedisulfonate, isethionate salts, and the like. The term “salt thereof” means a compound formed when a proton of an acid is replaced by a cation, such as a metal cation or an organic cation and the like. Where applicable, the salt is a pharmaceutically acceptable salt, although this is not required for salts of intermediate compounds that are not intended for administration to a patient. By way of example, salts of the present compounds include those wherein the compound is protonated by an inorganic or organic acid to form a cation, with the conjugate base of the inorganic or organic acid as the anionic component of the salt.

[0328] “Solvate” refers to a physical association of a compound or salt of the present disclosure with one or more solvent molecules, whether organic, inorganic, or a mixture of both. This physical association includes hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. The solvent molecules in the solvate may be present in a regular arrangement and / or a non-ordered arrangement. The solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules. “Solvate” encompasses both solution-phase and isolable solvates. Some examples of solvents include, but are not limited to, methanol, ethanol, isopropanol, N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water. When the solvent is water, the solvate formed is a hydrate (e.g., monohydrate, dihydrate, etc.). Exemplary solvates thus include, but are not limited to, hydrates, methanolates, ethanolates, isopropanolates, etc. Methods of solvation are generally known in the art.

[0329] “Stereoisomer” and “stereoisomers” refer to compounds that have same atomic connectivity but different atomic arrangement in space. Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers, and diastereomers. All forms such as racemates and optically pure stereoisomers of the compounds are contemplated herein. Chemical formulas and compounds which possess at least one stereogenic center, but are drawn without reference to stereochemistry, are intended to encompass both the racemic compound, as well as the separate stereoisomers, e.g., R- and / or S-stereoisomers, each permutation of diastereomers so long as those diastereomers are geometrically feasible, etc.

[0330] “Tautomer” refers to alternate forms of a molecule that differ only in electronic bonding of atoms and / or in the position of a proton, such as enol-keto, imine-enamine, and neutral / zwitterionic tautomers, or the tautomeric forms of heteroaryl groups containing a —N═C(H)—NH— ring atom arrangement, such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles. Other tautomeric ring atom arrangements are also possible. For example, compounds containing an acid and a base group within the same molecule depicted in neutral form may exist also in a zwitterionic form, as is the case for amino acid / ammonium carboxylate tautomers. A given chemical formula or name shall encompass all tautomeric forms thereof, insofar as they exist.

[0331] “Prodrug” is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term “prodrug” refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject, e.g., an ester, a phosphate ester, etc. but is converted in vivo to an active compound, for example, by hydrolysis to a free carboxylic acid or free hydroxyl group. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein. The term “prodrug” is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, ester (e.g., acetate, formate, benzoate, etc.), carbonate, carbamate, and dihydrogen phosphate derivatives of an alcohol, or amide (e.g., acetamide, formamide, benzamide, etc.), carbamate, etc. derivatives of an amine functional group in the active compound, and the like.

[0332] Compounds of the present disclosure may in some cases exist in a crystalline solid form or an amorphous solid form, and as such, these solid forms are contemplated herein. A “crystalline” solid is a type of solid whose fundamental three-dimensional structure contains a highly regular pattern of atoms or molecules—with long range order—forming a crystal lattice, and thus displays sharp characteristic crystalline peak(s) in its X-ray power diffraction (XRPD) pattern. In some instances, crystalline solids can exist in different crystalline forms known as “polymorphs,” which have the same chemical composition, but differ in packing, geometric arrangement, and other descriptive properties of the crystalline solid state. As such, polymorphs may have different solid-state physical properties to affect, for example, the solubility, dissolution rate, bioavailability, chemical and physical stability, flowability, and compressibility, etc. of the compound as well as the safety and efficacy of drug products based on the compound. In the process of preparing a polymorph, further purification, in terms of gross physical purity or optical purity, may be accomplished as well. As used herein, the term “amorphous” refers to a solid material having substantially no long range order in the position of its molecules—the molecules are arranged in a random manner so that there is effectively no well-defined arrangement, e.g., molecular packing, and no long range order. Amorphous solids are generally isotropic, i.e., exhibit similar properties in all directions and do not have definite melting points. For example, an amorphous material is a solid material having substantially no sharp characteristic crystalline peak(s) in its X-ray power diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or several broad peaks (e.g., halos) appear in its XRPD pattern. Broad peaks are characteristic of an amorphous solid. Thus, an “amorphous” subject compound / material is one characterized as having substantially no crystallinity—less than 10% crystallinity, less than 8% crystallinity, less than 6% crystallinity, less than 4% crystallinity, less than 2% crystallinity, less than 1% crystallinity, or 0% crystallinity—i.e., is at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or 100% amorphous, as determined for example by XRPD. For example, the % crystallinity can in some embodiments be determined by measuring the intensity of one or more peaks in the XRPD diffractogram compared to a reference peak, which may be that of an internal standard. Other characterization techniques, such as modulated differential scanning calorimetry (mDSC) analysis, Fourier transform infrared spectroscopy (FTIR), and other quantitative methods, may also be employed to determine the percent a subject compound / material is amorphous or crystalline, including quantitative methods which provide the above percentages in terms of weight percent.

[0333] It will be appreciated that the compounds herein can exist in different salt, solvate, stereoisomer, tautomer, crystalline / amorphous (including polymorphic) forms, and the present disclosure is intended to include all permutations thereof, such as a solvate of a pharmaceutically acceptable salt of a stereoisomer of the subject compound.

[0334] A “vapor” is a solid substance in the gas phase at a temperature lower than its critical temperature, meaning that the vapor can be condensed to a liquid by increasing the pressure on it without reducing the temperature.

[0335] An “aerosol”, as used herein, is a suspension of fine solid particles or liquid droplets in a gas phase (e.g., air, oxygen, helium, nitrous oxide, and other gases, as well as mixtures thereof). A “mist”, as used herein, is a subset of aerosols, differing from a vapor, and is a dispersion of liquid droplets (liquid phase) suspended in the gas phase (e.g., air, oxygen, helium, and mixtures thereof). The liquid droplets of an aerosol or mist can comprise a drug moiety dissolved in an aqueous liquid, organic solvent, or a mixture thereof. The gas phase of an aerosol or mist can comprise air, oxygen, helium, or other gases, including mixtures thereof. Mists do not comprise solid particulates. Aerosols and mists of the present disclosure can be generated by any suitable methods and devices, examples of which are set forth herein, e.g., through use of an inhaler or nebulizer.

[0336] As used herein, the term “inhalation session” describes a dosing event whereby the subject inhales a given dose of drug, irrespective of the number of breadths needed to inhale the given dose. For example, a subject prescribed to take 10 mg of a drug twice a day would undertake two inhalation sessions, each inhalation session providing 10 mg of the drug. The length of time and the number of breaths for each inhalation session would be dependent on factors such as the inhalation device used, the amount of drug that is drawn per breath, the concentration of the drug in the dosage form, the subject's breathing pattern, etc.

[0337] As used herein, the language “release period” describes the time window in which any compound described herein is released from the dosage form (e.g., the matrix) to afford plasma concentrations of compounds described herein. The start time of the release period is defined from the point of administration to a subject, which for oral administration is considered nearly equivalent to entry into the stomach, and initial dissolution by gastric enzymes and acid.

[0338] As used herein, the language “maximum sustained release” describes the release window for certain formulations of the present disclosure formulated to increase the release period to a maximum value, which for enteral routes is ultimately limited by the time the gastrointestinal tract naturally excretes all drugs with food.

[0339] The language “tamper resistance” is art-recognized to describe aspects of a drug formulation that make it more difficult to use the formulation to abuse the drug moiety of the formulation through extraction for intravenous use, or crushing for freebase use; and therefore reduce the risk for abuse of the drug.

[0340] As used herein, the term “steady” describes the stable or steady-state level of a molecule concentration, e.g., concentration of any compound described herein.

[0341] As used herein, the term “composition” is equivalent to the term “formulation.”

[0342] As used herein, the language “administration event” describes the administration of a given dose to a subject within a short window of time, e.g., less than 10 minutes. An oral administration event may be in the form of administration of, for example, one or more pills within a short window of time.

[0343] The term “treating” or “treatment” as used herein means the treating or treatment of a disease or medical condition in a patient, such as a mammal (particularly a human) that includes: ameliorating the disease or medical condition, such as, eliminating or causing regression of the disease or medical condition in a patient; suppressing the disease or medical condition, for example by, slowing or arresting the development of the disease or medical condition in a patient; or alleviating a symptom of the disease or medical condition in a patient. In some embodiments, prophylactic treatment can result in preventing the disease or medical condition from occurring, in a subject.

[0344] A “patient” or “subject,” used interchangeably herein, can be any mammal including, for example, a human or a non-human subject. A patient or subject can have a condition to be treated or can be susceptible to a condition to be treated.

[0345] As used herein, and unless otherwise specified, the terms “prevent,”“preventing” and “prevention” refer to the prevention of the onset, recurrence or spread of a disease, disorder, or condition, or of one or more symptoms thereof. The terms encompass the inhibition or reduction of a symptom of the particular disease, disorder, or condition. Subjects with familial history of a disease, disorder, or condition, in particular, are candidates for preventive regimens in some embodiments. In addition, subjects who have a history of recurring symptoms are also potential candidates for the prevention. In this regard, the term “prevention” may be interchangeably used with the term “prophylactic treatment.”

[0346] As used herein, and unless otherwise specified, the terms “manage,”“managing” and “management” refer to preventing or slowing the progression, spread or worsening of a disease, disorder, or condition, or of one or more symptoms thereof. Often, the beneficial effects that a subject derives from a prophylactic and / or therapeutic agent do not result in a cure of the disease, disorder, or condition. In this regard, the term “managing” encompasses treating a subject who had suffered from the particular disease, disorder, or condition in an attempt to prevent or minimize the recurrence of the disease, disorder, or condition, or of one or more symptoms thereof.

[0347] “Therapeutically effective amount” refers to an amount of a compound sufficient to treat a specified disorder or disease or one or more of its symptoms and / or to prevent the occurrence of the disease or disorder (prophylactically effective amount).

[0348] As used herein, and unless otherwise specified, a “prophylactically effective amount” of an active agent, is an amount sufficient to prevent a disease, disorder, or condition, or prevent its recurrence. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0349] The term “administration schedule” is a plan in which the type, amount, period, procedure, etc. of the drug in the drug treatment are shown in time series, and the dosage, administration method, administration order, administration date, and the like of each drug are indicated. The date specified to be administered is determined before the start of the drug administration. The administration is continued by repeating the course with the set of administration schedules as “courses”. A “continuous” administration schedule means administration every day without interruption during the treatment course. If the administration schedule follows an “intermittent” administration schedule, then days of administration may be followed by “rest days” or days of non-administration of drug within the course. A “drug holiday” indicates that the drug is not administered in a predetermined administration schedule. For example, after undergoing several courses of treatment, a subject may be prescribed a regulated drug holiday as part of the administration schedule, e.g., prior to re-recommencing active treatment.

[0350] The language “toxic spikes” is used herein to describe spikes in concentration of any compound described herein that would produce neurological side-effects of sedation or psychotomimetic effects, (e.g., hallucination, dizziness, and nausea), or any unwanted and / or unintended secondary effects caused by the administration of a medicament to an individual resulting in subjective experiences being qualitatively different from those of ordinary consciousness. These experiences can include derealization, depersonalization, hallucinations and / or sensory distortions in the visual, auditory, olfactory, tactile, proprioceptive and / or interoceptive spheres and / or any other perceptual modifications, and / or any other substantial subjective changes in cognition, memory, emotion and consciousness. Such side effects, when unwanted, unintended, and / or severe, can not only have immediate repercussions, but also effect treatment compliance. In particular, side effects may become more pronounced at blood concentration levels of about 250, 300, 400, 500 ng / L or more.

[0351] As used herein, and unless otherwise specified, a “neuropsychiatric disease or disorder” is a behavioral or psychological problem associated with a known neurological condition, and typically defined as a cluster of symptoms that co-exist. Examples of neuropsychiatric disorders include, but are not limited to, schizophrenia, cognitive deficits in schizophrenia, attention deficit disorder, attention deficit hyperactivity disorder, bipolar and manic disorders, depression or any combinations thereof.

[0352] “Inflammatory conditions” or “inflammatory disease,” as used herein, refers broadly to chronic or acute inflammatory diseases, including, but not limited to, rheumatic diseases (e.g., rheumatoid arthritis, osteoarthritis, psoriatic arthritis) spondyloarthropathies (e.g., ankylosing spondylitis, reactive arthritis, Reiter's syndrome), crystal arthropathies (e.g., gout, pseudogout, calcium pyrophosphate deposition disease), multiple sclerosis, Lyme disease, polymyalgia rheumatica; connective tissue diseases (e.g., systemic lupus erythematosus, systemic sclerosis, polymyositis, dermatomyositis, Sjogren's syndrome); vasculitides (e.g., polyarteritis nodosa, Wegener's granulomatosis, Churg-Strauss syndrome); inflammatory conditions including consequences of trauma or ischaemia, sarcoidosis; vascular diseases including atherosclerotic vascular disease, atherosclerosis, and vascular occlusive disease (e.g., atherosclerosis, ischaemic heart disease, myocardial infarction, stroke, peripheral vascular disease), and vascular stent restenosis; ocular diseases including uveitis, corneal disease, iritis, iridocyclitis, glaucoma, and cataracts.

[0353] All diseases and disorders listed herein may be defined as described in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), published by the American Psychiatric Association, or in International Classification of Diseases (ICD), published by the World Health Organization.

[0354] As used herein, the term “and / or” includes any and all combinations of one or more of the associated listed items. As used in the description herein and throughout the claims that follow, the meaning of “a”, “an”, and “the” includes plural reference as well as the singular reference unless the context clearly dictates otherwise. The term “about” in association with a numerical value means that the value varies up or down by 5%. For example, for a value of about 100, means 95 to 105 (or any value between 95 and 105).Compounds

[0355] The inventors have identified novel 2C—X type phenethylamine compounds, including those that demonstrate preferential binding to G-protein coupled receptors (GPCRs), e.g., 5-HT2 receptors, that are bioavailable (e.g., orally bioavailable), are distributed to the brain, have improved exposure (i.e., prevention of high drug concentrations (spiking) observed acutely after administration), and that possess advantageous enzymatic degradation profiles and clearance. As a result, the disclosed compounds may have reduced side effects and / or toxicity, reduced interpatient variability, fast onset, and may be relatively short acting, thereby enabling practical use in clinical settings. In addition to oral administration routes, these novel compounds may also possess properties, such as desirable lipophilicity, which enable their administration via inhalation or through transdermal routes, e.g., in the form of a transdermal patch. The novel 2C—X compounds are based on specific molecular modifications, e.g., involving deuteration and / or fluorination, to slow or shunt enzymatic degradation at specific sites, and in many cases introducing / maintaining metabolic soft spots at other sites—modifications which have been identified only after significant studies.Formula (I)

[0356] Disclosed herein is a compound according to Formula (I):or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof,

[0358] wherein:

[0359] X1 and X2 are independently hydrogen or deuterium;

[0360] Y1 and Y2 are independently hydrogen or deuterium;

[0361] R3 is hydrogen or deuterium;

[0362] R4 is halogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C3-C10 cycloalkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, —ORb, or —SRb;

[0363] R6 and R7 are independently hydrogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; or alternatively R6 and R7 together with the nitrogen atom attached thereto are optionally joined to form a substituted or unsubstituted heterocycloalkyl;

[0364] each Ra is independently a substituted or unsubstituted C1-C6 alkyl; and

[0365] Rb is hydrogen, deuterium, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, or a substituted or unsubstituted C3-C10 cycloalkyl;

[0366] with the proviso that at least one of X1, X2, Y1, Y2, R3, R4, R6, R7, and Ra comprises deuterium and / or R4 is selected from the group consisting of —SCF3, —SCF2H, —SCFH2, —SCH2CH2CF3, —SCH2CH2CF2H, —SCH2CH2CFH2, —SCH2CF2CF2H, —OCF3, —OCF2H, —OCFH2, —OCH2CH2CF3, —OCH2CH2CF2H, —OCH2CH2CFH2, —OCH2CF2CF2H, -cyclopentyl (—C5H9), and -A(CF2)m(CH2)nQ, wherein A is S, O, CH2, or CF2, m is 0 to 3, n is 0 to 6, and Q is —C≡CH or —C≡N.

[0367] X1 and X2 may be the same, or different. In some embodiments, X1 and X2 are the same. In some embodiments, X1 and X2 are hydrogen. In some embodiments, X1 and X2 are deuterium.

[0368] Y1 and Y2 may be the same, or different. In some embodiments, Y1 and Y2 are the same. In some embodiments, Y1 and Y2 are hydrogen. In some embodiments, Y1 and Y2 are deuterium.

[0369] In some embodiments, R3 is deuterium. In some embodiments, R3 is hydrogen.

[0370] In some embodiments, R4 is halogen, for example —Br, —F, —Cl, or —I.

[0371] In some embodiments, R4 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, R4 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. Preferred unsubstituted alkyl groups are methyl and t-butyl. In some embodiments, R4 is a substituted C1-C6 alkyl. Preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), cyano, polar substituents such as hydroxyl or polyether substituents, etc. The C1-C6 alkyl group may contain one, or more than one, substituent. In some embodiments, R4 is a substituted C1 alkyl group (i.e., a substituted methyl group), examples of which include, but are not limited to, —CDH2, —CD2H, —CD3, —CFH2, —CF2H, —CF3, and —CH2C≡N. In some embodiments, R4 is a substituted C2 alkyl group, examples of which may include, but are not limited to, —CDHCDH2, —CDHCD2H, —CD2CD3, —CH2CFH2, —CH2CF2H, —CH2CF3, and —CH2CH2C≡N. In some embodiments, R4 is not a substituted C2 alkyl group such as a C2 fluoroalkyl group. For example, in some embodiments, R4 is not —CH2CFH2, —CH2CF2H, or —CH2CF3. In some embodiments, R4 is a substituted C3 alkyl group, examples of which may include, but are not limited to —CH2CH2CF3, —CH2CH2CF2H, —CH2CH2CFH2, —CH2CF2CF2H, and —CH2CH2CH2C≡N. In some embodiments, R4 is not —CH2CH2CFH2.

[0372] In some embodiments, R4 is a substituted or unsubstituted C3-C10 cycloalkyl. In some embodiments, R4 is an unsubstituted C3-C10 cycloalkyl, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. In some embodiments, R4 is a substituted C3-C10 cycloalkyl. The cycloalkyl group may be substituted with any one or more substituents recited herein, examples of those substituents may include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The cycloalkyl group may contain one, or more than one, substituent.

[0373] In some embodiments, R4 is a substituted or unsubstituted alkenyl, e.g., a substituted or unsubstituted allyl, butenyl, crotyl, etc.

[0374] In some embodiments, R4 is a substituted or unsubstituted alkynyl, e.g., a substituted or unsubstituted acetylenyl, propargyl, homopropargyl, etc. In some embodiments, R4 is an unsubstituted alkynyl. In some embodiments, R4 is an unsubstituted acetylenyl (—C≡CH). In some embodiments, R4 is an unsubstituted propargyl (—CH2C≡CH). In some embodiments, R4 is —CH2CH2C≡CH. In some embodiments, R4 is —CH2CH2CH2C≡CH. In some embodiments, R4 is —CH2CH2CH2CH2C≡CH. In some embodiments, R4 is a substituted alkynyl. In some embodiments, R4 is a substituted propargyl (e.g., —CF2C≡CH). In some embodiments, R4 is —CF2CH2C≡CH. In some embodiments, R4 is —CF2CH2CH2C≡CH. In some embodiments, R4 is —CF2CH2CH2CH2C≡CH.

[0375] In some embodiments, R4 is —ORb or —SRb, wherein Rb is hydrogen, deuterium, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, or a substituted or unsubstituted C3-C10 cycloalkyl. In some embodiments, R4 is —ORb. In some embodiments, R4 is —SRb. In some embodiments, Rb is a substituted or unsubstituted C1-C6 alkyl, or a substituted or unsubstituted C3-C10 cycloalkyl, such as those substituted C1-C6 alkyl groups, unsubstituted C1-C6 alkyl groups, substituted C3-C10 cycloalkyl groups, or unsubstituted C3-C10 cycloalkyl groups defined and exemplified above.

[0376] In some embodiments, Rb is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, Rb is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. In some embodiments, Rb is a substituted C1-C6 alkyl. Preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), cyano, polar substituents such as hydroxyl or polyether substituents, etc. The C1-C6 alkyl group may contain one, or more than one, substituent. In some embodiments, Rb is a substituted C1 alkyl group, examples of which may include, but are not limited to, —CDH2, —CD2H, —CD3, —CFH2, —CF2H, —CF3, and —CH2C≡N. In some embodiments, Rb is a substituted C2 alkyl group, examples of which may include, but are not limited to, —CDHCDH2, —CDHCD2H, —CD2CD3, —CH2CFH2, —CH2CF2H, —CH2CF3, and —CH2CH2C≡N. In some embodiments, Rb is not a substituted C2 alkyl group such as a C2 fluoroalkyl group. For example, in some embodiments when R4 is —ORb or —SRb, Rb is not —CH2CFH2, —CH2CF2H, or —CH2CF3. In some embodiments, Rb is a substituted C3 alkyl group, examples of which may include, but are not limited to —CH2CH2CF3, —CH2CH2CF2H, —CH2CH2CFH2, —CH2CF2CF2H, and —CH2CH2CH2C≡N. In some embodiments, Rb is not —CH2CH2CFH2.

[0377] In some embodiments, Rb is a substituted or unsubstituted alkenyl, e.g., a substituted or unsubstituted allyl, butenyl, crotyl, etc.

[0378] In some embodiments, Rb is a substituted or unsubstituted alkynyl, e.g., a substituted or unsubstituted acetylenyl, propargyl, homopropargyl, etc. In some embodiments, Rb is an unsubstituted alkynyl. In some embodiments, Rb is an unsubstituted acetylenyl (—C≡CH). In some embodiments, Rb is an unsubstituted propargyl (—CH2C≡CH). In some embodiments, Rb is —CH2CH2C≡CH. In some embodiments, Rb is —CH2CH2CH2C≡CH. In some embodiments, Rb is —CH2CH2CH2CH2C≡CH. In some embodiments, Rb is a substituted alkynyl. In some embodiments, Rb is a substituted propargyl (e.g., —CF2C≡CH). In some embodiments, Rb is —CF2CH2C≡CH. In some embodiments, Rb is —CF2CH2CH2C≡CH. In some embodiments, Rb is —CF2CH2CH2CH2C≡CH.

[0379] In some embodiments, Rb is a substituted or unsubstituted cycloalkyl, for example a substituted or unsubstituted C3-C10 cycloalkyl, or a substituted or unsubstituted C4-C8 cycloalkyl, or a substituted or unsubstituted C5-C6 cycloalkyl. In some embodiments, Rb is an unsubstituted cycloalkyl (e.g., an unsubstituted C3-C10 cycloalkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, Rb is a substituted cycloalkyl (e.g., a substituted C3-C10 cycloalkyl). The cycloalkyl group may be substituted with any one or more substituents recited herein, examples of those substituents may include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The cycloalkyl group may contain one, or more than one, substituent.

[0380] In some embodiments, R4 is -A(CF2)m(CH2)nQ, wherein A is S, O, CH2, or CF2, m is 0 to 3, n is 0 to 6, and Q is —C≡CH or —C≡N. In some embodiments, A is S. In some embodiments, A is O. In some embodiments, A is CH2 (methylene). In some embodiments, A is CF2 (difluoromethylene). In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, when A is S or O, the sum of m+n is no more than 6, or no more than 5, or no more than 4, or no more than 3, or no more than 2, or no more than 1, or 0. In some embodiments, when A is CH2 or CF2, the sum of m+n is no more than 5, or no more than 4, or no more than 3, or no more than 2, or no more than 1, or 0. In some embodiments, Q is —C≡CH. In some embodiments, Q is —C≡N. Representative examples of the group -A(CF2)m(CH2)nQ include, but are not limited to, —SC≡CH, —SCH2C≡CH, —SCF2C≡CH, —SCH2C≡N, —SCH2CH2C≡CH, —SCF2CH2C≡CH, —SCH2CH2CH2C≡CH, —SCF2CH2CH2C≡CH, —OCH2C≡CH, —OC≡CH, —CH2C≡CH, —CF2C≡CH, —CH2CH2C≡CH, —CF2CH2C≡CH, —CH2CH2CH2C≡CH, —CF2CH2CH2C≡CH, —CH2CH2CH2CH2C≡CH, and —CF2CH2CH2CH2C≡CH.

[0381] In some embodiments, R4 is selected from the group consisting of —SMe, —SCD3, —SCF3, —SCF2H, —SCFH2, —SCH2CH2CF3, —SCH2CH2CF2H, —SCH2CH2CFH2, —SCH2CF2CF2H, —SCH2C≡CH, —SC≡CH, —SCF2C≡CH, —SCH2CH2CH2C≡CH, —SCF2CH2CH2C≡CH, —SEt, —Sn—Pr, -Me, —CD3, —CF3, -t-Bu, —C(CD3)3, -cyclopentyl, —OMe, —OCD3, —OCF3, —OCF2H, —OCFH2, —OCH2CH2CF3, —OCH2CH2CF2H, —OCH2CH2CFH2, —OCH2CF2CF2H, —OCH2C≡CH, —OC≡CH, —CH2CH2CH2CH2C≡CH, —CF2CH2CH2CH2C≡CH, —Cl, —I, or —Br. In some embodiments, R4 is selected from the group consisting of —SMe, —SCF3, —SCF2H, -Me, —OCD3, —CF3, -t-Bu, or -cyclopentyl. In some embodiments, R4 is selected from the group consisting of —SCF3, —SCF2H, —SCFH2, —SCH2CH2CF3, —SCH2CH2CF2H, —SCH2CH2CFH2, —SCH2CF2CF2H, —SCH2C≡CH, —SC≡CH, —SCF2C≡CH, —SCH2CH2CH2C≡CH, —SCF2CH2CH2C≡CH, —OCF3, —OCF2H, —OCFH2, —OCH2CH2CF3, —OCH2CH2CF2H, —OCH2CH2CFH2, —OCH2CF2CF2H, —OCH2C≡CH, —OC≡CH, —CH2CH2CH2CH2C≡CH, —CF2CH2CH2CH2C≡CH, and -cyclopentyl. When R4 is —SCF3, —SCF2H, —SCFH2, —SCH2CH2CF3, —SCH2CH2CF2H, —SCH2CH2CFH2, —SCH2CF2CF2H, —OCF3, —OCF2H, —OCFH2, —OCH2CH2CF3, —OCH2CH2CF2H, —OCH2CH2CFH2, —OCH2CF2CF2H, -cyclopentyl (—C5H9), or -A(CF2)m(CH2)nQ, wherein A is S, O, CH2, or CF2, m is 0 to 3, n is 0 to 6, and Q is —C≡CH or —C≡N, the other substituents (i.e., X1, X2, Y1, Y2, R3, R6, R7, and Ra) may, or may not, comprise deuterium. In some embodiments, R4 is selected from the group consisting of —SCF2H, —SCFH2, —SCH2CF2CF2H, —SCH2C≡CH, —SC≡CH, —SCF2C≡CH, —SCH2CH2CH2C≡CH, —SCF2CH2CH2C≡CH, —OCF3, —OCF2H, —OCFH2, —OCH2CF2CF2H, —OCH2C≡CH, —OC≡CH, —CH2CH2CH2CH2C≡CH, —CF2CH2CH2CH2C≡CH, and -cyclopentyl (—C5H9). When R4 is —SCF2H, —SCFH2, —SCH2CF2CF2H, —SCH2C≡CH, —SC≡CH, —SCF2C≡CH, —SCH2CH2CH2C≡CH, —SCF2CH2CH2C≡CH, —OCF3, —OCF2H, —OCFH2, —OCH2CF2CF2H, —OCH2C≡CH, —OC≡CH, —CH2CH2CH2CH2C≡CH, —CF2CH2CH2CH2C≡CH, or -cyclopentyl (—C5H9), the other substituents (i.e., X1, X2, Y1, Y2, R3, R6, R7, and Ra) may, or may not, comprise deuterium.

[0382] R6 and R7 may be the same, or different. In some embodiments, R6 and R7 are the same. For example, in some embodiments, both R6 and R7 are hydrogen. In some embodiments, R6 and R7 are different. For example, in some embodiments, R6 is hydrogen, and R7 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0383] In some embodiments, R6 and / or R7 is an unsubstituted C1-C6 alkyl, for example, an unsubstituted C1 alkyl, an unsubstituted C2 alkyl, an unsubstituted C3 alkyl, an unsubstituted C4 alkyl, an unsubstituted C5 alkyl, or an unsubstituted C6 alkyl. In some embodiments, R6 and / or R7 is an unsubstituted linear C2-C6 alkyl. In some embodiments, R6 and / or R7 is an unsubstituted branched C3-C10 alkyl. Examples of an unsubstituted C1-C6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, and isohexyl.

[0384] In some embodiments, R6 and / or R7 is a substituted C1-C6 alkyl, e.g., a substituted C1 alkyl, a substituted C2 alkyl, a substituted C3 alkyl, a substituted C4 alkyl, a substituted C5 alkyl, or a substituted C6 alkyl. The alkyl group may contain one, or more than one, substituent. The alkyl group may be substituted with any one or more substituents recited herein, examples of those substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, oxo, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), unsubstituted alkenyl, substituted alkenyl, unsubstituted alkynyl, substituted alkynyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. In some embodiments, R6 and / or R7 is a C1-C6 alkyl substituted with one or more deuterium atoms, examples of which include, but are not limited to, —CDH2, —CD2H, —CD3, —CD2CD3, and —CD2CD2CD3. In some embodiments, R6 and / or R7 is a C1-C6 alkyl substituted with one or more fluorine atoms, i.e., is a fluoroalkyl group. Examples of fluoroalkyl groups include, but are not limited to, —CH2F, —CHF2, —CF3, —CH2CH2F, —CH2CHF2, —CH2CF3, —CH2CH2CH2F, —CH2CH2CHF2, —CH2CH2CF3, —CH2CH2CH2CH2F, —CH2CH2CH2CHF2, —CH2CH2CH2CF3, —CH2CF2CHF2, —CH2CF2CF3, —CH(CF3)2, and —CH(CH3)CF3.

[0385] In some embodiments, R6 and / or R7 is a C1-C6 alkyl substituted with one or more deuterium atoms and one or more fluorine atoms, examples of which include, but are not limited to, —CD2CH2F, —CD2CHF2, —CD2CF3, —CD2CH2CH2F, —CD2CH2CHF2, —CD2CH2CF3, —CD2CD2CH2, —CD2CD2CHF2, —CD2CD2CF3, —CD2CH2CH2CH2F, —CD2CH2CH2CHF2, —CD2CH2CH2CF3, —CD2CD2CH2CH2F, —CD2CD2CH2CHF2, —CD2CD2CH2CF3, —CD2CD2CD2CH2F, —CD2CD2CD2CHF2, and —CD2CD2CD2CF3.

[0386] In some embodiments, R6 and / or R7 is a C1-C6 alkyl substituted with a substituted or unsubstituted cycloalkyl. The C1-C6 alkyl may be substituted with, e.g., a substituted or unsubstituted C3-C10 cycloalkyl, or a substituted or unsubstituted C4-C8 cycloalkyl, or a substituted or unsubstituted C5-C6 cycloalkyl. In some embodiments, the C1-C6 alkyl is substituted with an unsubstituted cycloalkyl (e.g., an unsubstituted C3-C10 cycloalkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the C1-C6 alkyl is substituted with a substituted cycloalkyl (e.g., a substituted C3-C10 cycloalkyl). The cycloalkyl group may be substituted with any one or more substituents recited herein, examples of those substituents may include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The cycloalkyl group may contain one, or more than one, substituent. In some embodiments, R6 and / or R7 is a C1 alkyl substituted with a substituted or unsubstituted cycloalkyl, with particular mention being made to cyclopropylmethyl (—CH2C3H5).

[0387] In some embodiments, R6 and / or R7 is a substituted or unsubstituted alkenyl, e.g., a substituted or unsubstituted allyl, butenyl, crotyl, etc.

[0388] In some embodiments, R6 and / or R7 is a substituted or unsubstituted alkynyl, e.g., a substituted or unsubstituted propargyl.

[0389] In some embodiments, R6 and / or R7 is a substituted or unsubstituted cycloalkyl, for example a substituted or unsubstituted C3-C10 cycloalkyl, or a substituted or unsubstituted C4-C8 cycloalkyl, or a substituted or unsubstituted C5-C6 cycloalkyl. In some embodiments, R6 and / or R7 is an unsubstituted cycloalkyl (e.g., an unsubstituted C3-C10 cycloalkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, R6 and / or R7 is a substituted cycloalkyl (e.g., a substituted C3-C10 cycloalkyl). The cycloalkyl group may be substituted with any one or more substituents recited herein, examples of those substituents may include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The cycloalkyl group may contain one, or more than one, substituent.

[0390] In some embodiments, R6 and / or R7 is a substituted or unsubstituted heterocycloalkyl. In some embodiments, the unsubstituted or substituted heterocycloalkyl group may be a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, or an 8-membered ring. In some embodiments, R6 and / or R7 is an unsubstituted heterocycloalkyl, such as those set forth herein, examples of which include, but are not limited to, aziridine, azetidine, pyrrolidine, isoindole, indole, dihydroindole, indazole, purine, carbazole, carboline, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, thiazolidine, morpholine, thiomorpholine, tetrahydrofuran, tetrahydropyran, and 1,3-dioxolane. In some embodiments, R6 and / or R7 is a substituted heterocycloalkyl. The substituent(s) may be any recited herein, including, but not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), oxo, and hydroxyl. The heterocycloalkyl group may contain one, or more than one, substituent.

[0391] In some embodiments, R6 and / or R7 is a substituted or unsubstituted aryl. In some embodiments, R6 and / or R7 is an unsubstituted aryl, examples of which include, but are not limited to, phenyl and naphthyl. In some embodiments, R6 and / or R7 is a substituted aryl. The substituent(s) may be any recited herein, including, but not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The aryl group may contain one, or more than one, substituent.

[0392] In some embodiments, R6 and / or R7 is a substituted or unsubstituted heteroaryl. In some embodiments, R6 and / or R7 is an unsubstituted heteroaryl, examples of which include, but are not limited to, pyrrolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzofuranyl, benzothiophenyl, thiophenyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, and pyrazolyl. In some embodiments, R6 and / or R7 is a substituted heteroaryl. The substituent(s) may be any recited herein, including, but not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The heteroaryl group may contain one, or more than one, substituent.

[0393] In some embodiments, R6 is hydrogen, and R7 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. In some embodiments, R6 is hydrogen, and R7 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, R6 is hydrogen, and R7 is an unsubstituted C1-C6 alkyl, a C1-C6 alkyl substituted with one or more deuterium atoms, a C1-C6 alkyl substituted with one or more fluorine atoms, or a C1-C6 alkyl substituted with a substituted or unsubstituted cycloalkyl. For example, in some embodiments, R6 is hydrogen, and R7 is methyl, ethyl, propyl, —CD3, or cyclopropylmethyl (—CH2C3H5).

[0394] In some embodiments, R6 and R7 together with the nitrogen atom attached thereto are joined to form a substituted or unsubstituted heterocycloalkyl. In some embodiments, R6 and R7 together with the nitrogen atom attached thereto are joined to form an unsubstituted heterocycloalkyl. The unsubstituted heterocycloalkyl group may be, e.g., a 3-membered ring, a 4-membered ring, 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, etc., which may be optionally fused to other ring(s). The unsubstituted heterocycloalkyl group contains a minimum of one nitrogen ring atom (the nitrogen atom intervening R6 and R7), and may optionally contain at least one additional hetero-ring atom, which may be one or more of nitrogen, sulfur, or oxygen, for a total of 1, 2, 3, or 4 hetero-ring atoms (at least one of which is a nitrogen ring atom). Examples of unsubstituted heterocycloalkyl groups formed from joining R6 and R7 together with the nitrogen atom attached thereto include, but are not limited to,

[0395] In some embodiments, R6 and R7 together with the nitrogen atom attached thereto are joined to form a substituted heterocycloalkyl. The substituted heterocycloalkyl group may be, e.g., a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, etc., which may be optionally fused to other ring(s). The substituted heterocycloalkyl group contains a minimum of one nitrogen ring atom (the nitrogen atom intervening R6 and R7), and may optionally contain additional hetero-ring atoms (e.g., nitrogen, sulfur, or oxygen) for a total of 1, 2, 3, or 4 hetero-ring atoms (at least one of which is a nitrogen ring atom). Examples of the substituted heterocycloalkyl group include, but are not limited to, aziridine, azetidine, pyrrolidine, isoindole, indole, dihydroindole, indazole, purine, carbazole, carboline, imidazolidine, imidazoline, piperidine, piperazine, indoline, 1,2,3,4-tetrahydroisoquinoline, thiazolidine, morpholine, or thiomorpholine, which is substituted with at least one substituent. The substituent(s) may be any recited herein, including, but not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, oxo, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), unsubstituted alkyl, substituted alkyl, unsubstituted alkenyl, substituted alkenyl, unsubstituted alkynyl, substituted alkynyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The substituted heterocycloalkyl formed from joining R6 and R7 together with the nitrogen atom attached thereto contains a heterocycloalkyl group substituted with one, two, three, four, or more substituents. The substituent may be located on a carbon ring atom or on a hetero-ring atom.

[0396] Examples of substituted heterocycloalkyl groups formed from joining R6 and R7 together with the nitrogen atom attached thereto include, but are not limited to,

[0397] Each Ra may be the same, or different. In some embodiments, each Ra is the same. Each Ra may be, independently, a substituted or unsubstituted C1-C6 alkyl, preferably a substituted or unsubstituted C1-C3 alkyl, preferably a substituted or unsubstituted C1 alkyl, examples of which include, but are not limited to, —CH3, —CDH2, —CD2H, —CD3, —CFH2, —CF2H, —CF3. In some embodiments, each Ra is —CH3. In some embodiments, each Ra is —CD3. In some embodiments, each Ra is different, e.g., one Ra is —CH3, while another is —CD3.

[0398] In some embodiments, Y1 and Y2 are each hydrogen or each deuterium; R3 is hydrogen; X1 and X2 are each hydrogen or each deuterium; each Ra is —CH3 or —CD3; R4 is —SMe, —SCD3, —SCF3, —SCF2H, —SCFH2, —SCH2CH2CF3, —SCH2CH2CF2H, —SCH2CH2CFH2, —SCH2CF2CF2H, —SCH2C≡CH, —SC≡CH, —SCF2C≡CH, —SCH2CH2CH2C≡CH, —SCF2CH2CH2C≡CH, —SEt, —Sn—Pr, -Me, —CD3, —CF3, -t-Bu, —C(CD3)3, -cyclopentyl, —OMe, —OCD3, —OCF3, —OCF2H, —OCFH2, —OCH2CH2CF3, —OCH2CH2CF2H, —OCH2CH2CFH2, —OCH2CF2CF2H, —OCH2C≡CH, —OC≡CH, —CH2CH2CH2CH2C≡CH, —CF2CH2CH2CH2C≡CH, —Cl, —I, or —Br, preferably R4 is —SCF3, —SCF2H, —SCFH2, —SCH2CH2CF3, —SCH2CH2CF2H, —SCH2CH2CFH2, —SCH2CF2CF2H, —SCH2C≡CH, —SC≡CH, —OCF3, —OCF2H, —OCFH2, —OCH2CH2CF3, —OCH2CH2CF2H, —OCH2CH2CFH2, —OCH2CF2CF2H, —OCH2C≡CH, —OC≡CH, —CH2CH2CH2CH2C≡CH, —CF2CH2CH2CH2C≡CH, and -cyclopentyl; R6 is hydrogen; and R7 is hydrogen or a substituted or unsubstituted C1-C6 alkyl.

[0399] As stated above, any of the above embodiments of the compound of Formula (I) may be provided as long as (i) at least one of X1, X2, Y1, Y2, R3, R4, R6, R7, and Ra comprises deuterium and / or (ii) R4 is selected from the group consisting of —SCF3, —SCF2H, —SCFH2, —SCH2CH2CF3, —SCH2CH2CF2H, —SCH2CH2CFH2, —SCH2CF2CF2H, —OCF3, —OCF2H, —OCFH2, —OCH2CH2CF3, —OCH2CH2CF2H, —OCH2CH2CFH2, —OCH2CF2CF2H, -cyclopentyl (—C5H9), and -A(CF2)m(CH2)nQ, wherein A is S, O, CH2, or CF2, m is 0 to 3, n is 0 to 6, and Q is —C≡CH or —C≡N. In some embodiments, in condition (ii), R4 is selected from the group consisting of —SCF2H, —SCFH2, —SCH2CF2CF2H, —SCH2C≡CH, —SC≡CH, —SCF2C≡CH, —SCH2CH2CH2C≡CH, —SCF2CH2CH2C≡CH, —OCF3, —OCF2H, —OCFH2, —OCH2CF2CF2H, —OCH2C≡CH, —OC≡CH, —CH2CH2CH2CH2C≡CH, —CF2CH2CH2CH2C≡CH, and -cyclopentyl (—C5H9). The above proviso written with “and / or” means that compounds fall within the scope when one of conditions (i) or (ii) is satisfied, or when both conditions (i) and (ii) are satisfied. For clarity, compounds in which condition (i) is satisfied, i.e., where at least one of X1, X2, Y1, Y2, R3, R4, R6, R7, and Ra comprises deuterium, do not require condition (ii) to be satisfied, e.g., R4 may or may not be selected from the group consisting of —SCF3, —SCF2H, —SCFH2, —SCH2CH2CF3, —SCH2CH2CF2H, —SCH2CH2CFH2, —SCH2CF2CF2H, —OCF3, —OCF2H, —OCFH2, —OCH2CH2CF3, —OCH2CH2CF2H, —OCH2CH2CFH2, —OCH2CF2CF2H, -cyclopentyl (—C5H9), and -A(CF2)m(CH2)nQ, wherein A is S, O, CH2, or CF2, m is 0 to 3, n is 0 to 6, and Q is —C≡CH or —C≡N. Likewise compounds in which condition (ii) is satisfied, e.g., when R4 is —SCF3, —SCF2H, —SCFH2, —SCH2CH2CF3, —SCH2CH2CF2H, —SCH2CH2CFH2, —SCH2CF2CF2H, —OCF3, —OCF2H, —OCFH2, —OCH2CH2CF3, —OCH2CH2CF2H, —OCH2CH2CFH2, —OCH2CF2CF2H, -cyclopentyl (—C5H9), or -A(CF2)m(CH2)nQ, wherein A is S, O, CH2, or CF2, m is 0 to 3, n is 0 to 6, and Q is —C≡CH or —C≡N, do not require condition (i) to be satisfied, i.e., the other substituents X1, X2, Y1, Y2, R3, R6, R7, and Ra may, or may not, comprise deuterium.Formula (II)

[0400] In some embodiments, the compound has a structure of Formula (II)or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof,

[0402] wherein:

[0403] X1 and X2 are independently hydrogen or deuterium;

[0404] Y1 and Y2 are independently hydrogen or deuterium;

[0405] R4 is halogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C3-C10 cycloalkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, —ORb, or —SRb; and

[0406] Rb is hydrogen, deuterium, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, or a substituted or unsubstituted C3-C10 cycloalkyl.

[0407] X1 and X2 may be the same, or different. In some embodiments, X1 and X2 are the same. In some embodiments, X1 and X2 are hydrogen. In some embodiments, X1 and X2 are deuterium.

[0408] Y1 and Y2 may be the same, or different. In some embodiments, Y1 and Y2 are the same. In some embodiments, Y1 and Y2 are hydrogen. In some embodiments, Y1 and Y2 are deuterium.

[0409] In some embodiments, R4 is halogen, for example —Br, —F, —Cl, or —I.

[0410] In some embodiments, R4 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, R4 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. Preferred unsubstituted alkyl groups are methyl and t-butyl. In some embodiments, R4 is a substituted C1-C6 alkyl. Preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), cyano, polar substituents such as hydroxyl or polyether substituents, etc. The C1-C6 alkyl group may contain one, or more than one, substituent. In some embodiments, R4 is a substituted C1 alkyl group (i.e., a substituted methyl group), examples of which include, but are not limited to, —CDH2, —CD2H, —CD3, —CFH2, —CF2H, —CF3, and —CH2C≡N. In some embodiments, R4 is a substituted C2 alkyl group, examples of which may include, but are not limited to, —CDHCDH2, —CDHCD2H, —CD2CD3, —CH2CFH2, —CH2CF2H, —CH2CF3, and —CH2CH2C≡N. In some embodiments, R4 is not a substituted C2 alkyl group such as a C2 fluoroalkyl group. For example, in some embodiments, R4 is not —CH2CFH2, —CH2CF2H, or —CH2CF3. In some embodiments, R4 is a substituted C3 alkyl group, examples of which may include, but are not limited to —CH2CH2CF3, —CH2CH2CF2H, —CH2CH2CFH2, —CH2CF2CF2H, and —CH2CH2CH2C≡N. In some embodiments, R4 is not —CH2CH2CFH2.

[0411] In some embodiments, R4 is a substituted or unsubstituted C3-C10 cycloalkyl. In some embodiments, R4 is an unsubstituted C3-C10 cycloalkyl, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. In some embodiments, R4 is a substituted C3-C10 cycloalkyl. The cycloalkyl group may be substituted with any one or more substituents recited herein, examples of those substituents may include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The cycloalkyl group may contain one, or more than one, substituent.

[0412] In some embodiments, R4 is a substituted or unsubstituted alkenyl, e.g., a substituted or unsubstituted allyl, butenyl, crotyl, etc.

[0413] In some embodiments, R4 is a substituted or unsubstituted alkynyl, e.g., a substituted or unsubstituted acetylenyl, propargyl, homopropargyl, etc. In some embodiments, R4 is an unsubstituted alkynyl. In some embodiments, R4 is an unsubstituted acetylenyl (—C≡CH). In some embodiments, R4 is an unsubstituted propargyl (—CH2C≡CH). In some embodiments, R4 is —CH2CH2C≡CH. In some embodiments, R4 is —CH2CH2CH2C≡CH. In some embodiments, R4 is —CH2CH2CH2CH2C≡CH. In some embodiments, R4 is a substituted alkynyl. In some embodiments, R4 is a substituted propargyl (e.g., —CF2C≡CH). In some embodiments, R4 is —CF2CH2C≡CH. In some embodiments, R4 is —CF2CH2CH2C≡CH. In some embodiments, R4 is —CF2CH2CH2CH2C≡CH.

[0414] In some embodiments, R4 is —ORb or —SRb, wherein Rb is hydrogen, deuterium, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, or a substituted or unsubstituted C3-C10 cycloalkyl. In some embodiments, R4 is —ORb. In some embodiments, R4 is —SRb. In some embodiments, Rb is a substituted or unsubstituted C1-C6 alkyl, or a substituted or unsubstituted C3-C10 cycloalkyl, such as those substituted C1-C6 alkyl groups, unsubstituted C1-C6 alkyl groups, substituted C3-C10 cycloalkyl groups, or unsubstituted C3-C10 cycloalkyl groups defined and exemplified above.

[0415] In some embodiments, Rb is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, Rb is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. In some embodiments, Rb is a substituted C1-C6 alkyl. Preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), cyano, polar substituents such as hydroxyl or polyether substituents, etc. The C1-C6 alkyl group may contain one, or more than one, substituent. In some embodiments, Rb is a substituted C1 alkyl group, examples of which may include, but are not limited to, —CDH2, —CD2H, —CD3, —CFH2, —CF2H, —CF3, and —CH2C≡N. In some embodiments, Rb is a substituted C2 alkyl group, examples of which may include, but are not limited to, —CDHCDH2, —CDHCD2H, —CD2CD3, —CH2CFH2, —CH2CF2H, —CH2CF3, and —CH2CH2C≡N. In some embodiments, Rb is not a substituted C2 alkyl group such as a C2 fluoroalkyl group. For example, in some embodiments when R4 is —ORb or —SRb, Rb is not —CH2CFH2, —CH2CF2H, or —CH2CF3. In some embodiments, Rb is a substituted C3 alkyl group, examples of which may include, but are not limited to —CH2CH2CF3, —CH2CH2CF2H, —CH2CH2CFH2, —CH2CF2CF2H, and —CH2CH2CH2C≡N. In some embodiments, Rb is not —CH2CH2CFH2.

[0416] In some embodiments, Rb is a substituted or unsubstituted alkenyl, e.g., a substituted or unsubstituted allyl, butenyl, crotyl, etc.

[0417] In some embodiments, Rb is a substituted or unsubstituted alkynyl, e.g., a substituted or unsubstituted acetylenyl, propargyl, homopropargyl, etc. In some embodiments, Rb is an unsubstituted alkynyl. In some embodiments, Rb is an unsubstituted acetylenyl (—C≡CH). In some embodiments, Rb is an unsubstituted propargyl (—CH2C≡CH). In some embodiments, Rb is —CH2CH2C≡CH. In some embodiments, Rb is —CH2CH2CH2C≡CH. In some embodiments, Rb is —CH2CH2CH2CH2C≡CH. In some embodiments, Rb is a substituted alkynyl. In some embodiments, Rb is a substituted propargyl (e.g., —CF2C≡CH). In some embodiments, Rb is —CF2CH2C≡CH. In some embodiments, Rb is —CF2CH2CH2C≡CH. In some embodiments, Rb is —CF2CH2CH2CH2C≡CH.

[0418] In some embodiments, Rb is a substituted or unsubstituted cycloalkyl, for example a substituted or unsubstituted C3-C10 cycloalkyl, or a substituted or unsubstituted C4-C8 cycloalkyl, or a substituted or unsubstituted C5-C6 cycloalkyl. In some embodiments, Rb is an unsubstituted cycloalkyl (e.g., an unsubstituted C3-C10 cycloalkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, Rb is a substituted cycloalkyl (e.g., a substituted C3-C10 cycloalkyl). The cycloalkyl group may be substituted with any one or more substituents recited herein, examples of those substituents may include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The cycloalkyl group may contain one, or more than one, substituent.

[0419] In some embodiments, R4 is -A(CF2)m(CH2)nQ, wherein A is S, O, CH2, or CF2, m is 0 to 3, n is 0 to 6, and Q is —C≡CH or —C≡N. In some embodiments, A is S. In some embodiments, A is O. In some embodiments, A is CH2 (methylene). In some embodiments, A is CF2 (difluoromethylene). In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, when A is S or O, the sum of m+n is no more than 6, or no more than 5, or no more than 4, or no more than 3, or no more than 2, or no more than 1, or 0. In some embodiments, when A is CH2 or CF2, the sum of m+n is no more than 5, or no more than 4, or no more than 3, or no more than 2, or no more than 1, or 0. In some embodiments, Q is —C≡CH. In some embodiments, Q is —C≡N. Representative examples of the group -A(CF2)m(CH2)nQ include, but are not limited to, —SC≡CH, —SCH2C≡CH, —SCF2C≡CH, —SCH2C≡N, —SCH2CH2C≡CH, —SCF2CH2C≡CH, —SCH2CH2CH2C≡CH, —SCF2CH2CH2C≡CH, —OCH2C≡CH, —OC≡CH, —CH2C≡CH, —CF2C≡CH, —CH2CH2C≡CH, —CF2CH2C≡CH, —CH2CH2CH2C≡CH, —CF2CH2CH2C≡CH, —CH2CH2CH2CH2C≡CH, and —CF2CH2CH2CH2C≡CH.

[0420] In some embodiments, R4 is selected from the group consisting of —SMe, —SCD3, —SCF3, —SCF2H, —SCFH2, —SCH2CH2CF3, —SCH2CH2CF2H, —SCH2CH2CFH2, —SCH2CF2CF2H, —SCH2C≡CH, —SC≡CH, —SCF2C≡CH, —SCH2CH2CH2C≡CH, —SCF2CH2CH2C≡CH, —SEt, —Sn—Pr, -Me, —CD3, —CF3, -t-Bu, —C(CD3)3, -cyclopentyl, —OMe, —OCD3, —OCF3, —OCF2H, —OCFH2, —OCH2CH2CF3, —OCH2CH2CF2H, —OCH2CH2CFH2, —OCH2CF2CF2H, —OCH2C≡CH, —OC≡CH, —CH2CH2CH2CH2C≡CH, —CF2CH2CH2CH2C≡CH, —Cl, —I, or —Br. In some embodiments, R4 is selected from the group consisting of —SMe, —SCF3, —SCF2H, -Me, —OCD3, —CF3, -t-Bu, or -cyclopentyl. In some embodiments, R4 is selected from the group consisting of —SCF3, —SCF2H, —SCFH2, —SCH2CH2CF3, —SCH2CH2CF2H, —SCH2CH2CFH2, —SCH2CF2CF2H, —SCH2C≡CH, —SC≡CH, —SCF2C≡CH, —SCH2CH2CH2C≡CH, —SCF2CH2CH2C≡CH, —OCF3, —OCF2H, —OCFH2, —OCH2CH2CF3, —OCH2CH2CF2H, —OCH2CH2CFH2, —OCH2CF2CF2H, —OCH2C≡CH, —OC≡CH, —CH2CH2CH2CH2C≡CH, —CF2CH2CH2CH2C≡CH, and -cyclopentyl. In some embodiments, R4 is selected from the group consisting of —SCF2H, —SCFH2, —SCH2CF2CF2H, —SCH2C≡CH, —SC≡CH, —SCF2C≡CH, —SCH2CH2CH2C≡CH, —SCF2CH2CH2C≡CH, —OCF3, —OCF2H, —OCFH2, —OCH2CF2CF2H, —OCH2C≡CH, —OC≡CH, —CH2CH2CH2CH2C≡CH, —CF2CH2CH2CH2C≡CH, and -cyclopentyl (—C5H9).

[0421] In some embodiments, Y1 and Y2 are each hydrogen or each deuterium, X1 and X2 are each hydrogen or each deuterium, and R4 is —SMe, —SCD3, —SCF3, —SCF2H, —SCFH2, —SCH2CH2CF3, —SCH2CH2CF2H, —SCH2CH2CFH2, —SCH2CF2CF2H, —SCH2C≡CH, —SC≡CH, —SCF2C≡CH, —SCH2CH2CH2C≡CH, —SCF2CH2CH2C≡CH, —SEt, —Sn—Pr, -Me, —CD3, —CF3, -t-Bu, —C(CD3)3, -cyclopentyl, —OMe, —OCD3, —OCF3, —OCF2H, —OCFH2, —OCH2CH2CF3, —OCH2CH2CF2H, —OCH2CH2CFH2, —OCH2CF2CF2H, —OCH2C≡CH, —OC≡CH, —CH2CH2CH2CH2C≡CH, —CF2CH2CH2CH2C≡CH, —Cl, —I, or —Br, preferably R4 is —SCF3, —SCF2H, —SCFH2, —SCH2CH2CF3, —SCH2CH2CF2H, —SCH2CH2CFH2, —SCH2CF2CF2H, —SCH2C≡CH, —SC≡CH, —OCF3, —OCF2H, —OCFH2, —OCH2CH2CF3, —OCH2CH2CF2H, —OCH2CH2CFH2, —OCH2CF2CF2H, —OCH2C≡CH, —OC≡CH, and -cyclopentyl.

[0422] The compounds of Formula (II) containing deuteration in the form of —OCD3 groups at the 2- and 5-position of the phenyl ring can have beneficial effects by slowing or shunting O-demethylation (primarily mediated by CYP2D6 enzymes) at these positions, thereby improving the pharmacokinetics, specifically the bioavailability, and safety as a result of lower exposure to potentially toxic metabolites.Formula (III)

[0423] In some embodiments, the compound has a structure of Formula (III):or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof,

[0425] wherein:

[0426] X1 and X2 are independently hydrogen or deuterium;

[0427] Y1 and Y2 are independently hydrogen or deuterium;

[0428] R4 is a C1-C6 alkyl substituted with one or more deuterium, a C3-C10 cycloalkyl substituted with one or more deuterium, —ORb, or —SRb;

[0429] each Ra is independently a substituted or unsubstituted C1-C6 alkyl; and

[0430] Rb is a C1-C6 alkyl substituted with one or more deuterium or a C3-C10 cycloalkyl substituted with one or more deuterium.

[0431] X1 and X2 may be the same, or different. In some embodiments, X1 and X2 are the same. In some embodiments, X1 and X2 are hydrogen. In some embodiments, X1 and X2 are deuterium.

[0432] Y1 and Y2 may be the same, or different. In some embodiments, Y1 and Y2 are the same. In some embodiments, Y1 and Y2 are hydrogen. In some embodiments, Y1 and Y2 are deuterium.

[0433] In some embodiments, R4 is a C1-C6 alkyl substituted with one or more deuterium, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl groups containing one or more deuterium substitutions. The alkyl group may contain one, or more than one, deuterium substituent, such as 1, 2, 3, 4, 5, 6, 7, 8, or 9 deuterium substituents. Exemplary C1-C6 alkyl groups substituted with one or more deuterium include, but are not limited to, —CD3 and —C(CD3)3.

[0434] In some embodiments, R4 is a C3-C10 cycloalkyl substituted with one or more deuterium, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cyclooctyl groups substituted with one or more deuterium. The cycloalkyl group may contain one, or more than one, substituent, such as 1, 2, 3, 4, 5, 6, 7, 8, or 9 deuterium substituents.

[0435] In some embodiments, R4 is —ORb, wherein Rb is a C1-C6 alkyl substituted with one or more deuterium, or a C3-C10 cycloalkyl substituted with one or more deuterium, such as those C1-C6 alkyl groups substituted with one or more deuterium or C3-C10 cycloalkyl groups substituted with one or more deuterium defined and exemplified above. In some embodiments, Rb is a C1 alkyl group substituted with one or more deuterium, for example, —CDH2, —CD2H, and —CD3. In some embodiments, Rb is a C2 alkyl group substituted with one or more deuterium, examples of which may include, but are not limited to, —CDHCDH2, —CDHCD2H, —CD2CD3. In some embodiments, Rb is a C3 alkyl group substituted with one or more deuterium. In some embodiments, R4 is —OCD3.

[0436] In some embodiments, R4 is —SRb, wherein Rb is a C1-C6 alkyl substituted with one or more deuterium, or a C3-C10 cycloalkyl substituted with one or more deuterium, such as those C1-C6 alkyl groups substituted with one or more deuterium or C3-C10 cycloalkyl groups substituted with one or more deuterium defined and exemplified above. In some embodiments, Rb is a C1 alkyl group substituted with one or more deuterium, for example, —CDH2, —CD2H, and —CD3. In some embodiments, Rb is a C2 alkyl group substituted with one or more deuterium, examples of which may include, but are not limited to, —CDHCDH2, —CDHCD2H, —CD2CD3. In some embodiments, Rb is a C3 alkyl group substituted with one or more deuterium. In some embodiments, R4 is —SCD3.

[0437] In some embodiments, R4 is selected from the group consisting of R4 is —SCD3, —CD3, —C(CD3)3, and —OCD3.

[0438] Each Ra may be the same, or different. In some embodiments, each Ra is the same. Each Ra may be, independently, a substituted or unsubstituted C1-C6 alkyl, preferably a substituted or unsubstituted C1-C3 alkyl, preferably a substituted or unsubstituted C1 alkyl, examples of which include, but are not limited to, —CH3, —CDH2, —CD2H, —CD3, —CFH2, —CF2H, —CF3. In some embodiments, each Ra is —CH3. In some embodiments, each Ra is —CD3. In some embodiments, each Ra is different, e.g., one Ra is —CH3, while another is —CD3.

[0439] In some embodiments, X1 and X2 are each hydrogen or each deuterium, Y1 and Y2 are each hydrogen or each deuterium, each Ra is —CH3, and R4 is —SCD3, —CD3, —C(CD3)3, or —OCD3.

[0440] The compounds of Formula (III) containing deuterated substituents (e.g., deuterated alkyl / cycloalkyl groups) in the R4 position of the phenyl ring can have beneficial effects by allowing for the incorporation of lipophilic groups for improved brain penetrability, while at the same time slowing or shunting metabolism at this position, for improved pharmacokinetics, specifically bioavailability.Formula (IV)

[0441] In some embodiments, the compound has a structure of Formula (IV):or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof,

[0443] wherein:

[0444] Y1 and Y2 are independently hydrogen or deuterium;

[0445] R4 is halogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C3-C10 cycloalkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, —ORb, or —SRb;

[0446] each Ra is independently a substituted or unsubstituted C1-C6 alkyl; and

[0447] Rb is hydrogen, deuterium, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, or a substituted or unsubstituted C3-C10 cycloalkyl.

[0448] Y1 and Y2 may be the same, or different. In some embodiments, Y1 and Y2 are the same. In some embodiments, Y1 and Y2 are hydrogen. In some embodiments, Y1 and Y2 are deuterium.

[0449] In some embodiments, R4 is halogen, for example —Br, —F, —Cl, or —I.

[0450] In some embodiments, R4 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, R4 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. Preferred unsubstituted alkyl groups are methyl and t-butyl. In some embodiments, R4 is a substituted C1-C6 alkyl. Preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), cyano, polar substituents such as hydroxyl or polyether substituents, etc. The C1-C6 alkyl group may contain one, or more than one, substituent. In some embodiments, R4 is a substituted C1 alkyl group (i.e., a substituted methyl group), examples of which include, but are not limited to, —CDH2, —CD2H, —CD3, —CFH2, —CF2H, —CF3, and —CH2C≡N. In some embodiments, R4 is a substituted C2 alkyl group, examples of which may include, but are not limited to, —CDHCDH2, —CDHCD2H, —CD2CD3, —CH2CFH2, —CH2CF2H, —CH2CF3, and —CH2CH2C≡N. In some embodiments, R4 is not a substituted C2 alkyl group such as a C2 fluoroalkyl group. For example, in some embodiments, R4 is not —CH2CFH2, —CH2CF2H, or —CH2CF3. In some embodiments, R4 is a substituted C3 alkyl group, examples of which may include, but are not limited to —CH2CH2CF3, —CH2CH2CF2H, —CH2CH2CFH2, —CH2CF2CF2H, and —CH2CH2CH2C≡N. In some embodiments, R4 is not —CH2CH2CFH2.

[0451] In some embodiments, R4 is a substituted or unsubstituted C3-C10 cycloalkyl. In some embodiments, R4 is an unsubstituted C3-C10 cycloalkyl, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. In some embodiments, R4 is a substituted C3-C10 cycloalkyl. The cycloalkyl group may be substituted with any one or more substituents recited herein, examples of those substituents may include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The cycloalkyl group may contain one, or more than one, substituent.

[0452] In some embodiments, R4 is a substituted or unsubstituted alkenyl, e.g., a substituted or unsubstituted allyl, butenyl, crotyl, etc.

[0453] In some embodiments, R4 is a substituted or unsubstituted alkynyl, e.g., a substituted or unsubstituted acetylenyl, propargyl, homopropargyl, etc. In some embodiments, R4 is an unsubstituted alkynyl. In some embodiments, R4 is an unsubstituted acetylenyl (—C≡CH). In some embodiments, R4 is an unsubstituted propargyl (—CH2C≡CH). In some embodiments, R4 is —CH2CH2C≡CH. In some embodiments, R4 is —CH2CH2CH2C≡CH. In some embodiments, R4 is —CH2CH2CH2CH2C≡CH. In some embodiments, R4 is a substituted alkynyl. In some embodiments, R4 is a substituted propargyl (e.g., —CF2C≡CH). In some embodiments, R4 is —CF2CH2C≡CH. In some embodiments, R4 is —CF2CH2CH2C≡CH. In some embodiments, R4 is —CF2CH2CH2CH2C≡CH.

[0454] In some embodiments, R4 is —ORb or —SRb, wherein Rb is hydrogen, deuterium, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, or a substituted or unsubstituted C3-C10 cycloalkyl. In some embodiments, R4 is —ORb. In some embodiments, R4 is —SRb. In some embodiments, Rb is a substituted or unsubstituted C1-C6 alkyl, or a substituted or unsubstituted C3-C10 cycloalkyl, such as those substituted C1-C6 alkyl groups, unsubstituted C1-C6 alkyl groups, substituted C3-C10 cycloalkyl groups, or unsubstituted C3-C10 cycloalkyl groups defined and exemplified above.

[0455] In some embodiments, Rb is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, Rb is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. In some embodiments, Rb is a substituted C1-C6 alkyl. Preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), cyano, polar substituents such as hydroxyl or polyether substituents, etc. The C1-C6 alkyl group may contain one, or more than one, substituent. In some embodiments, Rb is a substituted C1 alkyl group, examples of which may include, but are not limited to, —CDH2, —CD2H, —CD3, —CFH2, —CF2H, —CF3, and —CH2C≡N. In some embodiments, Rb is a substituted C2 alkyl group, examples of which may include, but are not limited to, —CDHCDH2, —CDHCD2H, —CD2CD3, —CH2CFH2, —CH2CF2H, —CH2CF3, and —CH2CH2C≡N. In some embodiments, Rb is not a substituted C2 alkyl group such as a C2 fluoroalkyl group. For example, in some embodiments when R4 is —ORb or —SRb, Rb is not —CH2CFH2, —CH2CF2H, or —CH2CF3. In some embodiments, Rb is a substituted C3 alkyl group, examples of which may include, but are not limited to —CH2CH2CF3, —CH2CH2CF2H, —CH2CH2CFH2, —CH2CF2CF2H, and —CH2CH2CH2C≡N. In some embodiments, Rb is not —CH2CH2CFH2.

[0456] In some embodiments, Rb is a substituted or unsubstituted alkenyl, e.g., a substituted or unsubstituted allyl, butenyl, crotyl, etc.

[0457] In some embodiments, Rb is a substituted or unsubstituted alkynyl, e.g., a substituted or unsubstituted acetylenyl, propargyl, homopropargyl, etc. In some embodiments, Rb is an unsubstituted alkynyl. In some embodiments, Rb is an unsubstituted acetylenyl (—C≡CH). In some embodiments, Rb is an unsubstituted propargyl (—CH2C≡CH). In some embodiments, Rb is —CH2CH2C≡CH. In some embodiments, Rb is —CH2CH2CH2C≡CH. In some embodiments, Rb is —CH2CH2CH2CH2C≡CH. In some embodiments, Rb is a substituted alkynyl. In some embodiments, Rb is a substituted propargyl (e.g., —CF2C≡CH). In some embodiments, Rb is —CF2CH2C≡CH. In some embodiments, Rb is —CF2CH2CH2C≡CH. In some embodiments, Rb is —CF2CH2CH2CH2C≡CH.

[0458] In some embodiments, Rb is a substituted or unsubstituted cycloalkyl, for example a substituted or unsubstituted C3-C10 cycloalkyl, or a substituted or unsubstituted C4-C8 cycloalkyl, or a substituted or unsubstituted C5-C6 cycloalkyl. In some embodiments, Rb is an unsubstituted cycloalkyl (e.g., an unsubstituted C3-C10 cycloalkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, Rb is a substituted cycloalkyl (e.g., a substituted C3-C10 cycloalkyl). The cycloalkyl group may be substituted with any one or more substituents recited herein, examples of those substituents may include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The cycloalkyl group may contain one, or more than one, substituent.

[0459] In some embodiments, R4 is -A(CF2)m(CH2)nQ, wherein A is S, O, CH2, or CF2, m is 0 to 3, n is 0 to 6, and Q is —C≡CH or —C≡N. In some embodiments, A is S. In some embodiments, A is O. In some embodiments, A is CH2 (methylene). In some embodiments, A is CF2 (difluoromethylene). In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, when A is S or O, the sum of m+n is no more than 6, or no more than 5, or no more than 4, or no more than 3, or no more than 2, or no more than 1, or 0. In some embodiments, when A is CH2 or CF2, the sum of m+n is no more than 5, or no more than 4, or no more than 3, or no more than 2, or no more than 1, or 0. In some embodiments, Q is —C≡CH. In some embodiments, Q is —C≡N. Representative examples of the group -A(CF2)m(CH2)nQ include, but are not limited to, —SC≡CH, —SCH2C≡CH, —SCF2C≡CH, —SCH2C≡N, —SCH2CH2C≡CH, —SCF2CH2C≡CH, —SCH2CH2CH2C≡CH, —SCF2CH2CH2C≡CH, —OCH2C≡CH, —OC≡CH, —CH2C≡CH, —CF2C≡CH, —CH2CH2C≡CH, —CF2CH2C≡CH, —CH2CH2CH2C≡CH, —CF2CH2CH2C≡CH, —CH2CH2CH2CH2C≡CH, and —CF2CH2CH2CH2C≡CH.

[0460] In some embodiments, R4 is selected from the group consisting of —SMe, —SCD3, —SCF3, —SCF2H, —SCFH2, —SCH2CH2CF3, —SCH2CH2CF2H, —SCH2CH2CFH2, —SCH2CF2CF2H, —SCH2C≡CH, —SC≡CH, —SCF2C≡CH, —SCH2CH2CH2C≡CH, —SCF2CH2CH2C≡CH, —SEt, —Sn—Pr, -Me, —CD3, —CF3, -t-Bu, —C(CD3)3, -cyclopentyl, —OMe, —OCD3, —OCF3, —OCF2H, —OCFH2, —OCH2CH2CF3, —OCH2CH2CF2H, —OCH2CH2CFH2, —OCH2CF2CF2H, —OCH2C≡CH, —OC≡CH, —CH2CH2CH2CH2C≡CH, —CF2CH2CH2CH2C≡CH, —Cl, —I, or —Br. In some embodiments, R4 is selected from the group consisting of —SMe, —SCF3, —SCF2H, -Me, —OCD3, —CF3, -t-Bu, or -cyclopentyl. In some embodiments, R4 is selected from the group consisting of —SCF3, —SCF2H, —SCFH2, —SCH2CH2CF3, —SCH2CH2CF2H, —SCH2CH2CFH2, —SCH2CF2CF2H, —SCH2C≡CH, —SC≡CH, —SCF2C≡CH, —SCH2CH2CH2C≡CH, —SCF2CH2CH2C≡CH, —OCF3, —OCF2H, —OCFH2, —OCH2CH2CF3, —OCH2CH2CF2H, —OCH2CH2CFH2, —OCH2CF2CF2H, —OCH2C≡CH, —OC≡CH, —CH2CH2CH2CH2C≡CH, —CF2CH2CH2CH2C≡CH, and -cyclopentyl. In some embodiments, R4 is selected from the group consisting of —SCF2H, —SCFH2, —SCH2CF2CF2H, —SCH2C≡CH, —SC≡CH, —SCF2C≡CH, —SCH2CH2CH2C≡CH, —SCF2CH2CH2C≡CH, —OCF3, —OCF2H, —OCFH2, —OCH2CF2CF2H, —OCH2C≡CH, —OC≡CH, —CH2CH2CH2CH2C≡CH, —CF2CH2CH2CH2C≡CH, and -cyclopentyl (—C5H9).

[0461] Each Ra may be the same, or different. In some embodiments, each Ra is the same. Each Ra may be, independently, a substituted or unsubstituted C1-C6 alkyl, preferably a substituted or unsubstituted C1-C3 alkyl, preferably a substituted or unsubstituted C1 alkyl, examples of which include, but are not limited to, —CH3, —CDH2, —CD2H, —CD3, —CFH2, —CF2H, —CF3. In some embodiments, each Ra is —CH3. In some embodiments, each Ra is —CD3. In some embodiments, each Ra is different, e.g., one Ra is —CH3, while another is —CD3.

[0462] In some embodiments, Y1 and Y2 are each hydrogen or each deuterium, each Ra is —CH3 or —CD3; and R4 is —SMe, —SCD3, —SCF3, —SCF2H, —SCFH2, —SCH2CH2CF3, —SCH2CH2CF2H, —SCH2CH2CFH2, —SCH2CF2CF2H, —SCH2C≡CH, —SC≡CH, —SCF2C≡CH, —SCH2CH2CH2C≡CH, —SCF2CH2CH2C≡CH, —SEt, —Sn—Pr, -Me, —CD3, —CF3, -t-Bu, —C(CD3)3, -cyclopentyl, —OMe, —OCD3, —OCF3, —OCF2H, —OCFH2, —OCH2CH2CF3, —OCH2CH2CF2H, —OCH2CH2CFH2, —OCH2CF2CF2H, —OCH2C≡CH, —OC≡CH, —CH2CH2CH2CH2C≡CH, —CF2CH2CH2CH2C≡CH, —Cl, —I, or —Br, preferably R4 is —SCF3, —SCF2H, —SCFH2, —SCH2CH2CF3, —SCH2CH2CF2H, —SCH2CH2CFH2, —SCH2CF2CF2H, —SCH2C≡CH, —SC≡CH, —OCF3, —OCF2H, —OCFH2, —OCH2CH2CF3, —OCH2CH2CF2H, —OCH2CH2CFH2, —OCH2CF2CF2H, —OCH2C≡CH, —OC≡CH, and -cyclopentyl.

[0463] The compounds of Formula (IV) containing deuteration in the ethylene fragment that links the amino group with the benzene ring in phenethylamines, e.g., α-carbon deuteration, may advantageously slow enzymatic degradation compared to compounds which may otherwise be susceptible to MAO mediated deamination / oxidation processes, thereby improving bioavailability as well as enhancing brain levels of the active compound, with the objective to effectively reduce therapeutic doses and to prevent high drug concentrations (“spiking”) observed acutely after administration. As a result, such compounds may result in reduced side effects and toxicity, such as acute adverse effects, including anxiety, fear, tachycardia, hypertension, increased body temperature, nausea and vomiting, as well as toxicity caused by activation of 5-HT2B receptors associated with valvular heart disease.Formula (V)

[0464] In some embodiments, the compound has a structure of Formula (V):or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof,

[0466] wherein:

[0467] X1 and X2 are independently hydrogen or deuterium;

[0468] Y1 and Y2 are independently hydrogen or deuterium;

[0469] R4 is halogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C3-C10 cycloalkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, —ORb, or —SRb;

[0470] R6 is hydrogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl;

[0471] R7 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl;

[0472] or alternatively R6 and R7 together with the nitrogen atom attached thereto are optionally joined to form a substituted or unsubstituted heterocycloalkyl;

[0473] each Ra is independently a substituted or unsubstituted C1-C6 alkyl; and

[0474] Rb is hydrogen, deuterium, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, or a substituted or unsubstituted C3-C10 cycloalkyl;

[0475] In some embodiments, at least one of X1, X2, Y1, Y2, R3, R4, R6, R7, and Ra comprises deuterium and / or R4 is selected from the group consisting of —SCF3, —SCF2H, —SCFH2, —SCH2CH2CF3, —SCH2CH2CF2H, —SCH2CH2CFH2, —SCH2CF2CF2H, —OCF3, —OCF2H, —OCFH2, —OCH2CH2CF3, —OCH2CH2CF2H, —OCH2CH2CFH2, —OCH2CF2CF2H, -cyclopentyl (—C5H9), and -A(CF2)m(CH2)nQ, wherein A is S, O, CH2, or CF2, m is 0 to 3, n is 0 to 6, and Q is —C≡CH or —C≡N.

[0476] X1 and X2 may be the same, or different. In some embodiments, X1 and X2 are the same. In some embodiments, X1 and X2 are hydrogen. In some embodiments, X1 and X2 are deuterium.

[0477] Y1 and Y2 may be the same, or different. In some embodiments, Y1 and Y2 are the same. In some embodiments, Y1 and Y2 are hydrogen. In some embodiments, Y1 and Y2 are deuterium.

[0478] In some embodiments, R4 is halogen, for example —Br, —F, —Cl, or —I.

[0479] In some embodiments, R4 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, R4 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. Preferred unsubstituted alkyl groups are methyl and t-butyl. In some embodiments, R4 is a substituted C1-C6 alkyl. Preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), cyano, polar substituents such as hydroxyl or polyether substituents, etc. The C1-C6 alkyl group may contain one, or more than one, substituent. In some embodiments, R4 is a substituted C1 alkyl group (i.e., a substituted methyl group), examples of which include, but are not limited to, —CDH2, —CD2H, —CD3, —CFH2, —CF2H, —CF3, and —CH2C≡N. In some embodiments, R4 is a substituted C2 alkyl group, examples of which may include, but are not limited to, —CDHCDH2, —CDHCD2H, —CD2CD3, —CH2CFH2, —CH2CF2H, —CH2CF3, and —CH2CH2C≡N. In some embodiments, R4 is not a substituted C2 alkyl group such as a C2 fluoroalkyl group. For example, in some embodiments, R4 is not —CH2CFH2, —CH2CF2H, or —CH2CF3. In some embodiments, R4 is a substituted C3 alkyl group, examples of which may include, but are not limited to —CH2CH2CF3, —CH2CH2CF2H, —CH2CH2CFH2, —CH2CF2CF2H, and —CH2CH2CH2C≡N. In some embodiments, R4 is not —CH2CH2CFH2.

[0480] In some embodiments, R4 is a substituted or unsubstituted C3-C10 cycloalkyl. In some embodiments, R4 is an unsubstituted C3-C10 cycloalkyl, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. In some embodiments, R4 is a substituted C3-C10 cycloalkyl. The cycloalkyl group may be substituted with any one or more substituents recited herein, examples of those substituents may include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The cycloalkyl group may contain one, or more than one, substituent.

[0481] In some embodiments, R4 is a substituted or unsubstituted alkenyl, e.g., a substituted or unsubstituted allyl, butenyl, crotyl, etc.

[0482] In some embodiments, R4 is a substituted or unsubstituted alkynyl, e.g., a substituted or unsubstituted acetylenyl, propargyl, homopropargyl, etc. In some embodiments, R4 is an unsubstituted alkynyl. In some embodiments, R4 is an unsubstituted acetylenyl (—C≡CH). In some embodiments, R4 is an unsubstituted propargyl (—CH2C≡CH). In some embodiments, R4 is —CH2CH2C≡CH. In some embodiments, R4 is —CH2CH2CH2C≡CH. In some embodiments, R4 is —CH2CH2CH2CH2C≡CH. In some embodiments, R4 is a substituted alkynyl. In some embodiments, R4 is a substituted propargyl (e.g., —CF2C≡CH). In some embodiments, R4 is —CF2CH2C≡CH. In some embodiments, R4 is —CF2CH2CH2C≡CH. In some embodiments, R4 is —CF2CH2CH2CH2C≡CH.

[0483] In some embodiments, R4 is —ORb or —SRb, wherein Rb is hydrogen, deuterium, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, or a substituted or unsubstituted C3-C10 cycloalkyl. In some embodiments, R4 is —ORb. In some embodiments, R4 is —SRb. In some embodiments, Rb is a substituted or unsubstituted C1-C6 alkyl, or a substituted or unsubstituted C3-C10 cycloalkyl, such as those substituted C1-C6 alkyl groups, unsubstituted C1-C6 alkyl groups, substituted C3-C10 cycloalkyl groups, or unsubstituted C3-C10 cycloalkyl groups defined and exemplified above.

[0484] In some embodiments, Rb is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, Rb is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. In some embodiments, Rb is a substituted C1-C6 alkyl. Preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), cyano, polar substituents such as hydroxyl or polyether substituents, etc. The C1-C6 alkyl group may contain one, or more than one, substituent. In some embodiments, Rb is a substituted C1 alkyl group, examples of which may include, but are not limited to, —CDH2, —CD2H, —CD3, —CFH2, —CF2H, —CF3, and —CH2C≡N. In some embodiments, Rb is a substituted C2 alkyl group, examples of which may include, but are not limited to, —CDHCDH2, —CDHCD2H, —CD2CD3, —CH2CFH2, —CH2CF2H, —CH2CF3, and —CH2CH2C≡N. In some embodiments, Rb is not a substituted C2 alkyl group such as a C2 fluoroalkyl group. For example, in some embodiments when R4 is —ORb or —SRb, Rb is not —CH2CFH2, —CH2CF2H, or —CH2CF3. In some embodiments, Rb is a substituted C3 alkyl group, examples of which may include, but are not limited to —CH2CH2CF3, —CH2CH2CF2H, —CH2CH2CFH2, —CH2CF2CF2H, and —CH2CH2CH2C≡N. In some embodiments, Rb is not —CH2CH2CFH2.

[0485] In some embodiments, Rb is a substituted or unsubstituted alkenyl, e.g., a substituted or unsubstituted allyl, butenyl, crotyl, etc.

[0486] In some embodiments, Rb is a substituted or unsubstituted alkynyl, e.g., a substituted or unsubstituted acetylenyl, propargyl, homopropargyl, etc. In some embodiments, Rb is an unsubstituted alkynyl. In some embodiments, Rb is an unsubstituted acetylenyl (—C≡CH). In some embodiments, Rb is an unsubstituted propargyl (—CH2C≡CH). In some embodiments, Rb is —CH2CH2C≡CH. In some embodiments, Rb is —CH2CH2CH2C≡CH. In some embodiments, Rb is —CH2CH2CH2CH2C≡CH. In some embodiments, Rb is a substituted alkynyl. In some embodiments, Rb is a substituted propargyl (e.g., —CF2C≡CH). In some embodiments, Rb is —CF2CH2C≡CH. In some embodiments, Rb is —CF2CH2CH2C≡CH. In some embodiments, Rb is —CF2CH2CH2CH2C≡CH.

[0487] In some embodiments, Rb is a substituted or unsubstituted cycloalkyl, for example a substituted or unsubstituted C3-C10 cycloalkyl, or a substituted or unsubstituted C4-C5 cycloalkyl, or a substituted or unsubstituted C5-C6 cycloalkyl. In some embodiments, Rb is an unsubstituted cycloalkyl (e.g., an unsubstituted C3-C10 cycloalkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, Rb is a substituted cycloalkyl (e.g., a substituted C3-C10 cycloalkyl). The cycloalkyl group may be substituted with any one or more substituents recited herein, examples of those substituents may include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The cycloalkyl group may contain one, or more than one, substituent.

[0488] In some embodiments, R4 is -A(CF2)m(CH2)nQ, wherein A is S, O, CH2, or CF2, m is 0 to 3, n is 0 to 6, and Q is —C≡CH or —C≡N. In some embodiments, A is S. In some embodiments, A is O. In some embodiments, A is CH2 (methylene). In some embodiments, A is CF2 (difluoromethylene). In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, when A is S or O, the sum of m+n is no more than 6, or no more than 5, or no more than 4, or no more than 3, or no more than 2, or no more than 1, or 0. In some embodiments, when A is CH2 or CF2, the sum of m+n is no more than 5, or no more than 4, or no more than 3, or no more than 2, or no more than 1, or 0. In some embodiments, Q is —C≡CH. In some embodiments, Q is —C≡N. Representative examples of the group -A(CF2)m(CH2)nQ include, but are not limited to, —SC≡CH, —SCH2C≡CH, —SCF2C≡CH, —SCH2C≡N, —SCH2CH2C≡CH, —SCF2CH2C≡CH, —SCH2CH2CH2C≡CH, —SCF2CH2CH2C≡CH, —OCH2C≡CH, —OC≡CH, —CH2C≡CH, —CF2C≡CH, —CH2CH2C≡CH, —CF2CH2C≡CH, —CH2CH2CH2C≡CH, —CF2CH2CH2C≡CH, —CH2CH2CH2CH2C≡CH, and —CF2CH2CH2CH2C≡CH.

[0489] In some embodiments, R4 is selected from the group consisting of —SMe, —SCD3, —SCF3, —SCF2H, —SCFH2, —SCH2CH2CF3, —SCH2CH2CF2H, —SCH2CH2CFH2, —SCH2CF2CF2H, —SCH2C≡CH, —SC≡CH, —SCF2C≡CH, —SCH2CH2CH2C≡CH, —SCF2CH2CH2C≡CH, —SEt, —Sn—Pr, -Me, —CD3, —CF3, -t-Bu, —C(CD3)3, -cyclopentyl, —OMe, —OCD3, —OCF3, —OCF2H, —OCFH2, —OCH2CH2CF3, —OCH2CH2CF2H, —OCH2CH2CFH2, —OCH2CF2CF2H, —OCH2C≡CH, —OC≡CH, —CH2CH2CH2CH2C≡CH, —CF2CH2CH2CH2C≡CH, —Cl, —I, or —Br. In some embodiments, R4 is selected from the group consisting of —SMe, —SCF3, —SCF2H, -Me, —OCD3, —CF3, -t-Bu, or -cyclopentyl. In some embodiments, R4 is selected from the group consisting of —SCF3, —SCF2H, —SCFH2, —SCH2CH2CF3, —SCH2CH2CF2H, —SCH2CH2CFH2, —SCH2CF2CF2H, —SCH2C≡CH, —SC≡CH, —SCF2C≡CH, —SCH2CH2CH2C≡CH, —SCF2CH2CH2C≡CH, —OCF3, —OCF2H, —OCFH2, —OCH2CH2CF3, —OCH2CH2CF2H, —OCH2CH2CFH2, —OCH2CF2CF2H, —OCH2C≡CH, —OC≡CH, —CH2CH2CH2CH2C≡CH, —CF2CH2CH2CH2C≡CH, and -cyclopentyl. In embodiments where R4 is —SCF3, —SCF2H, —SCFH2, —SCH2CH2CF3, —SCH2CH2CF2H, —SCH2CH2CFH2, —SCH2CF2CF2H, —OCF3, —OCF2H, —OCFH2, —OCH2CH2CF3, —OCH2CH2CF2H, —OCH2CH2CFH2, —OCH2CF2CF2H, -cyclopentyl (—C5H9), or -A(CF2)m(CH2)nQ, (wherein A is S, O, CH2, or CF2, m is 0 to 3, n is 0 to 6, and Q is —C≡CH or —C≡N), the other substituents (i.e., X1, X2, Y1, Y2, R6, R7, and Ra) may, or may not, comprise deuterium. In some embodiments, R4 is selected from the group consisting of —SCF2H, —SCFH2, —SCH2CF2CF2H, —SCH2C≡CH, —SC≡CH, —SCF2C≡CH, —SCH2CH2CH2C≡CH, —SCF2CH2CH2C≡CH, —OCF3, —OCF2H, —OCFH2, —OCH2CF2CF2H, —OCH2C≡CH, —OC≡CH, —CH2CH2CH2CH2C≡CH, —CF2CH2CH2CH2C≡CH, and -cyclopentyl (—C5H9). In embodiments where R4 is —SCF2H, —SCFH2, —SCH2CF2CF2H, —SCH2C≡CH, —SC≡CH, —SCF2C≡CH, —SCH2CH2CH2C≡CH, —SCF2CH2CH2C≡CH, —OCF3, —OCF2H, —OCFH2, —OCH2CF2CF2H, —OCH2C≡CH, —OC≡CH, —CH2CH2CH2CH2C≡CH, —CF2CH2CH2CH2C≡CH, or -cyclopentyl (—C6H9), the other substituents (i.e., X1, X2, Y1, Y2, R3, R6, R7, and Ra) may, or may not, comprise deuterium.

[0490] R6 and R7 may be the same, or different. In some embodiments, R6 and R7 are the same. In some embodiments, R6 and R7 are different. For example, in some embodiments, R6 is hydrogen, and R7 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0491] In some embodiments, R6 and / or R7 is an unsubstituted C1-C6 alkyl, for example, an unsubstituted C1 alkyl, an unsubstituted C2 alkyl, an unsubstituted C3 alkyl, an unsubstituted C4 alkyl, an unsubstituted C5 alkyl, or an unsubstituted C6 alkyl. In some embodiments, R6 and / or R7 is an unsubstituted linear C2-C6 alkyl. In some embodiments, R6 and / or R7 is an unsubstituted branched C3-C10 alkyl. Examples of an unsubstituted C1-C10 alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, and isohexyl.

[0492] In some embodiments, R6 and / or R7 is a substituted C1-C6 alkyl, e.g., a substituted C1 alkyl, a substituted C2 alkyl, a substituted C3 alkyl, a substituted C4 alkyl, a substituted C5 alkyl, or a substituted C6 alkyl. The alkyl group may contain one, or more than one, substituent. The alkyl group may be substituted with any one or more substituents recited herein, examples of those substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, oxo, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), unsubstituted alkenyl, substituted alkenyl, unsubstituted alkynyl, substituted alkynyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. In some embodiments, R6 and / or R7 is a C1-C6 alkyl substituted with one or more deuterium atoms, examples of which include, but are not limited to, —CDH2, —CD2H, —CD3, —CD2CD3, and —CD2CD2CD3. In some embodiments, R6 and / or R7 is a C1-C6 alkyl substituted with one or more fluorine atoms, i.e., is a fluoroalkyl group. Examples of fluoroalkyl groups include, but are not limited to, —CH2F, —CHF2, —CF3, —CH2CH2F, —CH2CHF2, —CH2CF3, —CH2CH2CH2F, —CH2CH2CHF2, —CH2CH2CF3, —CH2CH2CH2CH2F, —CH2CH2CH2CHF2, —CH2CH2CH2CF3, —CH2CF2CHF2, —CH2CF2CF3, —CH(CF3)2, and —CH(CH3)CF3.

[0493] In some embodiments, R6 and / or R7 is a C1-C6 alkyl substituted with one or more deuterium atoms and one or more fluorine atoms, examples of which include, but are not limited to, —CD2CH2F, —CD2CHF2, —CD2CF3, —CD2CH2CH2F, —CD2CH2CHF2, —CD2CH2CF3, —CD2CD2CH2, —CD2CD2CHF2, —CD2CD2CF3, —CD2CH2CH2CH2F, —CD2CH2CH2CHF2, —CD2CH2CH2CF3, —CD2CD2CH2CH2F, —CD2CD2CH2CHF2, —CD2CD2CH2CF3, —CD2CD2CD2CH2F, —CD2CD2CD2CHF2, and —CD2CD2CD2CF3.

[0494] In some embodiments, R6 and / or R7 is a C1-C6 alkyl substituted with a substituted or unsubstituted cycloalkyl. The C1-C6 alkyl may be substituted with, e.g., a substituted or unsubstituted C3-C10 cycloalkyl, or a substituted or unsubstituted C4-C8 cycloalkyl, or a substituted or unsubstituted C5-C6 cycloalkyl. In some embodiments, the C1-C6 alkyl is substituted with an unsubstituted cycloalkyl (e.g., an unsubstituted C3-C10 cycloalkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the C1-C6 alkyl is substituted with a substituted cycloalkyl (e.g., a substituted C3-C10 cycloalkyl). The cycloalkyl group may be substituted with any one or more substituents recited herein, examples of those substituents may include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The cycloalkyl group may contain one, or more than one, substituent. In some embodiments, R6 and / or R7 is a C1 alkyl substituted with a substituted or unsubstituted cycloalkyl, with particular mention being made to cyclopropylmethyl (—CH2C3H5).

[0495] In some embodiments, R6 and / or R7 is a substituted or unsubstituted alkenyl, e.g., a substituted or unsubstituted allyl, butenyl, crotyl, etc.

[0496] In some embodiments, R6 and / or R7 is a substituted or unsubstituted alkynyl, e.g., a substituted or unsubstituted propargyl.

[0497] In some embodiments, R6 and / or R7 is a substituted or unsubstituted cycloalkyl, for example a substituted or unsubstituted C3-C10 cycloalkyl, or a substituted or unsubstituted C4-C8 cycloalkyl, or a substituted or unsubstituted C5-C6 cycloalkyl. In some embodiments, R6 and / or R7 is an unsubstituted cycloalkyl (e.g., an unsubstituted C3-C10 cycloalkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, R6 and / or R7 is a substituted cycloalkyl (e.g., a substituted C3-C10 cycloalkyl). The cycloalkyl group may be substituted with any one or more substituents recited herein, examples of those substituents may include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The cycloalkyl group may contain one, or more than one, substituent.

[0498] In some embodiments, R6 and / or R7 is a substituted or unsubstituted heterocycloalkyl. In some embodiments, the unsubstituted or substituted heterocycloalkyl group may be a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, or an 8-membered ring. In some embodiments, R6 and / or R7 is an unsubstituted heterocycloalkyl, such as those set forth herein, examples of which include, but are not limited to, aziridine, azetidine, pyrrolidine, isoindole, indole, dihydroindole, indazole, purine, carbazole, carboline, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, thiazolidine, morpholine, thiomorpholine, tetrahydrofuran, tetrahydropyran, and 1,3-dioxolane. In some embodiments, R6 and / or R7 is a substituted heterocycloalkyl. The substituent(s) may be any recited herein, including, but not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), oxo, and hydroxyl. The heterocycloalkyl group may contain one, or more than one, substituent.

[0499] In some embodiments, R6 and / or R7 is a substituted or unsubstituted aryl. In some embodiments, R6 and / or R7 is an unsubstituted aryl, examples of which include, but are not limited to, phenyl and naphthyl. In some embodiments, R6 and / or R7 is a substituted aryl. The substituent(s) may be any recited herein, including, but not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The aryl group may contain one, or more than one, substituent.

[0500] In some embodiments, R6 and / or R7 is a substituted or unsubstituted heteroaryl. In some embodiments, R6 and / or R7 is an unsubstituted heteroaryl, examples of which include, but are not limited to, pyrrolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzofuranyl, benzothiophenyl, thiophenyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, and pyrazolyl. In some embodiments, R6 and / or R7 is a substituted heteroaryl. The substituent(s) may be any recited herein, including, but not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The heteroaryl group may contain one, or more than one, substituent.

[0501] In some embodiments, R6 is hydrogen, and R7 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. In some embodiments, R6 is hydrogen, and R7 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, R6 is hydrogen, and R7 is an unsubstituted C1-C6 alkyl, a C1-C6 alkyl substituted with one or more deuterium atoms, a C1-C6 alkyl substituted with one or more fluorine atoms, or a C1-C6 alkyl substituted with a substituted or unsubstituted cycloalkyl. For example, in some embodiments, R6 is hydrogen, and R7 is methyl, ethyl, propyl, —CD3, or cyclopropylmethyl (—CH2C3H5).

[0502] In some embodiments, R6 and R7 together with the nitrogen atom attached thereto are joined to form a substituted or unsubstituted heterocycloalkyl. In some embodiments, R6 and R7 together with the nitrogen atom attached thereto are joined to form an unsubstituted heterocycloalkyl. The unsubstituted heterocycloalkyl group may be, e.g., a 3-membered ring, a 4-membered ring, 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, etc., which may be optionally fused to other ring(s). The unsubstituted heterocycloalkyl group contains a minimum of one nitrogen ring atom (the nitrogen atom intervening R6 and R7), and may optionally contain at least one additional hetero-ring atom, which may be one or more of nitrogen, sulfur, or oxygen, for a total of 1, 2, 3, or 4 hetero-ring atoms (at least one of which is a nitrogen ring atom). Examples of unsubstituted heterocycloalkyl groups formed from joining R6 and R7 together with the nitrogen atom attached thereto include, but are not limited to,

[0503] In some embodiments, R6 and R7 together with the nitrogen atom attached thereto are joined to form a substituted heterocycloalkyl. The substituted heterocycloalkyl group may be, e.g., a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, etc., which may be optionally fused to other ring(s). The substituted heterocycloalkyl group contains a minimum of one nitrogen ring atom (the nitrogen atom intervening R6 and R7), and may optionally contain additional hetero-ring atoms (e.g., nitrogen, sulfur, or oxygen) for a total of 1, 2, 3, or 4 hetero-ring atoms (at least one of which is a nitrogen ring atom). Examples of the substituted heterocycloalkyl group include, but are not limited to, aziridine, azetidine, pyrrolidine, isoindole, indole, dihydroindole, indazole, purine, carbazole, carboline, imidazolidine, imidazoline, piperidine, piperazine, indoline, 1,2,3,4-tetrahydroisoquinoline, thiazolidine, morpholine, or thiomorpholine, which is substituted with at least one substituent. The substituent(s) may be any recited herein, including, but not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, oxo, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), unsubstituted alkyl, substituted alkyl, unsubstituted alkenyl, substituted alkenyl, unsubstituted alkynyl, substituted alkynyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The substituted heterocycloalkyl formed from joining R6 and R7 together with the nitrogen atom attached thereto contains a heterocycloalkyl group substituted with one, two, three, four, or more substituents. The substituent may be located on a carbon ring atom or on a hetero-ring atom.

[0504] Examples of substituted heterocycloalkyl groups formed from joining R6 and R7 together with the nitrogen atom attached thereto include, but are not limited to,

[0505] Each Ra may be the same, or different. In some embodiments, each Ra is the same. Each Ra may be, independently, a substituted or unsubstituted C1-C6 alkyl, preferably a substituted or unsubstituted C1-C3 alkyl, preferably a substituted or unsubstituted C1 alkyl, examples of which include, but are not limited to, —CH3, —CDH2, —CD2H, —CD3, —CFH2, —CF2H, —CF3. In some embodiments, each Ra is —CH3. In some embodiments, each Ra is —CD3. In some embodiments, each Ra is different, e.g., one Ra is —CH3, while another is —CD3.

[0506] In some embodiments, Y1 and Y2 are each hydrogen or each deuterium; X1 and X2 are each hydrogen or each deuterium; each Ra is —CH3 or —CD3; R4 is —SMe, —SCD3, —SCF3, —SCF2H, —SCFH2, —SCH2CH2CF3, —SCH2CH2CF2H, —SCH2CH2CFH2, —SCH2CF2CF2H, —SCH2C≡CH, —SC≡CH, —SCF2C≡CH, —SCH2CH2CH2C≡CH, —SCF2CH2CH2C≡CH, —SEt, —Sn—Pr, -Me, —CD3, —CF3, -t-Bu, —C(CD3)3, -cyclopentyl, —OMe, —OCD3, —OCF3, —OCF2H, —OCFH2, —OCH2CH2CF3, —OCH2CH2CF2H, —OCH2CH2CFH2, —OCH2CF2CF2H, —OCH2C≡CH, —OC≡CH, —CH2CH2CH2CH2C≡CH, —CF2CH2CH2CH2C≡CH, —Cl, —I, or —Br, preferably R4 is —SCF3, —SCF2H, —SCFH2, —SCH2CH2CF3, —SCH2CH2CF2H, —SCH2CH2CFH2, —SCH2CF2CF2H, —SCH2C≡CH, —SC≡CH, —OCF3, —OCF2H, —OCFH2, —OCH2CH2CF3, —OCH2CH2CF2H, —OCH2CH2CFH2, —OCH2CF2CF2H, —OCH2C≡CH, —OC≡CH, and -cyclopentyl; R6 is hydrogen; and R7 is a substituted or unsubstituted C1-C6 alkyl.

[0507] In some embodiments, the compound of Formula (V) may be provided with the following proviso: (i) at least one of X1, X2, Y1, Y2, R4, R6, R7, and Ra comprises deuterium and / or (ii) R4 is selected from the group consisting of —SCF3, —SCF2H, —SCFH2, —SCH2CH2CF3, —SCH2CH2CF2H, —SCH2CH2CFH2, —SCH2CF2CF2H, —OCF3, —OCF2H, —OCFH2, —OCH2CH2CF3, —OCH2CH2CF2H, —OCH2CH2CFH2, —OCH2CF2CF2H, -cyclopentyl (—C5H9), and -A(CF2)m(CH2)nQ, wherein A is S, O, CH2, or CF2, m is 0 to 3, n is 0 to 6, and Q is —C≡CH or —C≡N. In some embodiments, in condition (ii), R4 is selected from the group consisting of —SCF2H, —SCFH2, —SCH2CF2CF2H, —SCH2C≡CH, —SC≡CH, —SCF2C≡CH, —SCH2CH2CH2C≡CH, —SCF2CH2CH2C≡CH, —OCF3, —OCF2H, —OCFH2, —OCH2CF2CF2H, —OCH2C≡CH, —OC≡CH, —CH2CH2CH2CH2C≡CH, —CF2CH2CH2CH2C≡CH, and -cyclopentyl (—C5H9). The above proviso written with “and / or” means that compounds fall within the scope when one of conditions (i) or (ii) is satisfied, or when both conditions (i) and (ii) are satisfied. For clarity, compounds in which condition (i) is satisfied, i.e., where at least one of X1, X2, Y1, Y2, R3, R4, R6, R7, and Ra comprises deuterium, do not require condition (ii) to be satisfied, e.g., R4 may or may not be selected from the group consisting of —SCF3, —SCF2H, —SCFH2, —SCH2CH2CF3, —SCH2CH2CF2H, —SCH2CH2CFH2, —SCH2CF2CF2H, —OCF3, —OCF2H, —OCFH2, —OCH2CH2CF3, —OCH2CH2CF2H, —OCH2CH2CFH2, —OCH2CF2CF2H, -cyclopentyl (—C5H9), and -A(CF2)m(CH2)nQ, wherein A is S, O, CH2, or CF2, m is 0 to 3, n is 0 to 6, and Q is —C≡CH or —C≡N. Likewise compounds in which condition (ii) is satisfied, e.g., when R4 is —SCF3, —SCF2H, —SCFH2, —SCH2CH2CF3, —SCH2CH2CF2H, —SCH2CH2CFH2, —SCH2CF2CF2H, —OCF3, —OCF2H, —OCFH2, —OCH2CH2CF3, —OCH2CH2CF2H, —OCH2CH2CFH2, —OCH2CF2CF2H, -cyclopentyl (—C5H9), or -A(CF2)m(CH2)nQ, wherein A is S, O, CH2, or CF2, m is 0 to 3, n is 0 to 6, and Q is —C≡CH or —C≡N, do not require condition (i) to be satisfied, i.e., the other substituents X1, X2, Y1, Y2, R3, R6, R7 and Ra may, or may not, comprise deuterium. In some embodiments, a compound of Formula (V) is provided without the above proviso.

[0508] In some embodiments, the compound, e.g., the compound of Formula (I) through (V) is selected from the group consisting of:or a pharmaceutically acceptable salt, solvate, or prodrug thereof.The compound number, IUPAC name, and substituent listing for several of the above-identified compounds are provided in Table 1.TABLE 1Exemplary compounds of Formula (I)Formula (I)Compound number and nameX1, X2Y1, Y2R3R4Ra, RaR6, R7I-12-(2,5-dimethoxy-4-H, HH, HH—SCF3—Me,H, H((trifluoromethyl)thio)phenyl)ethan-1-—MeamineI-22-(2,5-dimethoxy-4-((3,3,3-H, HH, HH—SCH2CH2CF3—Me,H, Htrifluoropropyl)thio)phenyl)ethan-1-—MeamineI-32-(4-((3,3-difluoropropyl)thio)-2,5-H, HH, HH—SCH2CH2CF2H—Me,H, Hdimethoxyphenyl)ethan-1-amine—MeI-42-(4-((3-fluoropropyl)thio)-2,5-H, HH, HH—SCH2CH2CFH2—Me,H, Hdimethoxyphenyl)ethan-1-amine—MeI-52-(2,5-dimethoxy-4-(3,3,3-H, HH, HH—OCH2CH2CF3—Me,H, Htrifluoropropoxy)phenyl)ethan-1-—MeamineI-62-(4-(3,3-difluoropropoxy)-2,5-H, HH, HH—OCH2CH2CF2H—Me,H, Hdimethoxyphenyl)ethan-1-amine—MeI-72-(4-(3-fluoropropoxy)-2,5-H, HH, HH—OCH2CH2CFH2—Me,H, Hdimethoxyphenyl)ethan-1-amine—MeI-82-(4-((difluoromethyl)thio)-2,5-H, HH, HH—SCF2H—Me,H, Hdimethoxyphenyl)ethan-1-amine—MeI-92-(4-((fluoromethyl)thio)-2,5-H, HH, HH—SCFH2—Me,H, Hdimethoxyphenyl)ethan-1-amine—MeI-102-(2,5-dimethoxy-4-((2,2,3,3-H, HH, HH—SCH2CF2CF2H—Me,H, Htetrafluoropropyl)thio)phenyl)ethan-1-—MeamineI-112-(2,5-dimethoxy-4-(prop-2-yn-1-H, HH, HH—SCH2C≡CH—Me,H, Hylthio)phenyl)ethan-1-amine—MeI-122-(4-(ethynylthio)-2,5-H, HH, HH—SC≡CH—Me,H, Hdimethoxyphenyl)ethan-1-amine—MeI-132-(4-cyclopentyl-2,5-H, HH, HH—C5H9—Me,H, Hdimethoxyphenyl)ethan-1-amine—MeII-12-(2,5-bis(methoxy-d3)-4-H, HH, HH—SMe—CD3,H, H(methylthio)phenyl)ethan-1-amine—CD3II-22-(2,5-bis(methoxy-d3)-4-H, HH, HH—Me—CD3,H, Hmethylphenyl)ethan-1-amine—CD3II-32-(4-(tert-butyl)-2,5-bis(methoxy-H, HH, HH-t-Bu—CD3,H, Hd3)phenyl)ethan-1-amine—CD3II-42-(4-cyclopentyl-2,5-bis(methoxy-H, HH, HH—C5H9—CD3,H, Hd3)phenyl)ethan-1-amine—CD3II-52-(2,5-bis(methoxy-d3)-4-D, DH, HH—OCF3—CD3,H, H(trifluoromethoxy)phenyl)ethan-1,1-—CD3d2-1-amineII-62-(2,4,5-tris(methoxy-D, DH, HH—OCD3—CD3,H, Hd3)phenyl)ethan-1,1-d2-1-amine—CD3II-72-(4-bromo-2,5-bis(methoxy-H, HH, HH—Br—CD3,H, Hd3)phenyl)ethan-1-amine—CD3II-82-(4-bromo-2,5-bis(methoxy-D, DH, HH—Br—CD3,H, Hd3)phenyl)ethan-1,1-d2-1-amine—CD3II-92-(4-iodo-2,5-bis(methoxy-H, HH, HH—I—CD3,H, Hd3)phenyl)ethan-1-amine—CD3II-102-(2,5-bis(methoxy-d3)-4-H, HH, HH—SCF3—CD3,H, H((trifluoromethyl)thio)phenyl)ethan-1-—CD3amineII-112-(2,5-bis(methoxy-d3)-4-D, DH, HH—S—n—Pr—CD3,H, H(propylthio)phenyl)ethan-1,1-d2-1-—CD3amineII-122-(2,5-bis(methoxy-d3)-4-D, DD, DH—OCF3—CD3,H, H(trifluoromethoxy)phenyl)ethan-—CD31,1,2,2-d4-1-amineII-132-(2,4,5-tris(methoxy-D, DD, DH—OCD3—CD3,H, Hd3)phenyl)ethan-1,1,2,2-d4-1-amine—CD3II-142-(4-bromo-2,5-bis(methoxy-D, DD, DH—Br—CD3,H, Hd3)phenyl)ethan-1,1,2,2-d4-1-amine—CD3II-152-(2,5-bis(methoxy-d3)-4-D, DD, DH—S—n—Pr—CD3,H, H(propylthio)phenyl)ethan-1,1,2,2-d4-—CD31-amineII-162-(2,5-bis(methoxy-d3)-4-((3,3,3-H, HH, HH—SCH2CH2CF3—CD3,H, Htrifluoropropyl)thio)phenyl)ethan-1-—CD3amineII-172-(4-((3,3-difluoropropyl)thio)-2,5-H, HH, HH—SCH2CH2CF2H—CD3,H, Hbis(methoxy-d3)phenyl)ethan-1-—CD3amineII-182-(4-((3-fluoropropyl)thio)-2,5-H, HH, HH—SCH2CH2CFH2—CD3,H, Hbis(methoxy-d3)phenyl)ethan-1-—CD3amineII-192-(2,5-bis(methoxy-d3)-4-(3,3,3-H, HH, HH—OCH2CH2CF3—CD3,H, Htrifluoropropoxy)phenyl)ethan-1-—CD3amineII-202-(4-(3,3-difluoropropoxy)-2,5-H, HH, HH—OCH2CH2CF2H—CD3,H, Hbis(methoxy-d3)phenyl)ethan-1-—CD3amineII-212-(4-(3-fluoropropoxy)-2,5-H, HH, HH—OCH2CH2CFH2—CD3,H, Hbis(methoxy-d3)phenyl)ethan-1-—CD3amineII-222-(4-((difluoromethyl)thio)-2,5-H, HH, HH—SCF2H—CD3,H, Hbis(methoxy-d3)phenyl)ethan-1-—CD3amineII-232-(2,5-bis(methoxy-d3)-4-H, HH, HH—CF3—CD3,H, H(trifluoromethyl)phenyl)ethan-1-amine—CD3III-12-(2,5-dimethoxy-4-(methyl-H, HH, HH—CD3—Me,H, Hd3)phenyl)ethan-1-amine—MeIII-22-(2,5-dimethoxy-4-(2-(methyl-H, HH, HH—C(CD3)3—Me,H, Hd3)propan-2-yl-1,1,1,3,3,3-—Med6)phenyl)ethan-1-amineIV-12-(2,5-dimethoxy-4-D, DH, HH—SMe—Me,H, H(methylthio)phenyl)ethan-1,1-d2-1-—MeamineIV-22-(2,5-dimethoxy-4-D, DH, HH—S—n—Pr—Me,H, H(propylthio)phenyl)ethan-1,1-d2-1-—MeamineIV-32-(2,5-dimethoxy-4-D, DH, HH—CF3—Me,H, H(trifluoromethyl)phenyl)ethan-1,1-d2-—Me1-amineIV-42-(2,4,5-trimethoxyphenyl)ethan-1,1-D, DH, HH—OMe—Me,H, Hd2-1-amine—MeIV-52-(4-bromo-2,5-D, DH, HH—Br—Me,H, Hdimethoxyphenyl)ethan-1,1-d2-1-—MeamineIV-62-(2,5-dimethoxy-4-D, DH, HH—SCF3—Me,H, H((trifluoromethyl)thio)phenyl)ethan-—Me1,1-d2-1-amineIV-72-(2,5-dimethoxy-4-D, DH, HH—OCF3—Me,H, H(trifluoromethoxy)phenyl)ethan-1,1-—Med2-1-amineIV-82-(2,5-dimethoxy-4-D, DD, DH—SMe—Me,H, H(methylthio)phenyl)ethan-1,1,2,2-d4-—Me1-amineIV-92-(2,5-dimethoxy-4-D, DD, DH—S—n—Pr—Me,H, H(propylthio)phenyl)ethan-1,1,2,2-d4-1-—MeamineIV-102-(2,5-dimethoxy-4-D, DD, DH—CF3—Me,H, H(trifluoromethyl)phenyl)ethan-1,1,2,2-—Med4-1-amineIV-112-(2,4,5-trimethoxyphenyl)ethan-D, DD, DH—OMe—Me,H, H1,1,2,2-d4-1-amine—MeIV-122-(4-bromo-2,5-D, DD, DH—Br—Me,H, Hdimethoxyphenyl)ethan-1,1,2,2-d4-1-—MeamineIV-132-(2,5-dimethoxy-4-D, DD, DH—SCF3—Me,H, H((trifluoromethyl)thio)phenyl)ethan-—Me1,1,2,2-d4-1-amineIV-142-(2,5-dimethoxy-4-D, DD, DH—OCF3—Me,H, H(trifluoromethoxy)phenyl)ethan-1,1,2,2-—Med4-1-amineIV-152-(4-((difluoromethyl)thio)-2,5-D, DH, HH—SCF2H—Me,H, Hdimethoxyphenyl)ethan-1,1-d2-1-amine—MeIV-162-(4-((difluoromethyl)thio)-2,5-D, DD, DH—SCF2H—Me,H, Hdimethoxyphenyl)ethan-1,1,2,2-d4-1-—MeamineV-1N-(cyclopropylmethyl)-2-(2,5-dimethoxy-H, HH, HH—SCF3—Me,—H,4-((trifluoromethyl)thio)phenyl)ethan-1-—Me—CH2C3H5amineV-22-(2,5-dimethoxy-4-H, HH, HH—SCF3—Me,—H,((trifluoromethyl)thio)phenyl)-N-—Me—Memethylethan-1-amineV-32-(2,5-dimethoxy-4-H, HH, HH—SCF3—Me,—H,((trifluoromethyl)thio)phenyl)-N-—Me—Etethylethan-1-amineV-4N-(2,5-dimethoxy-4-H, HH, HH—SCF3—Me,—H,((trifluoromethyl)thio)phenethyl)propan-—Me-n-Pr1-amineV-52-(2,5-dimethoxy-4-H, HH, HH—SCF3—Me,—H,((trifluoromethyl)thio)phenyl)-N-(methyl-—Me—CD3d3)ethan-1-amineV-62-(2,5-bis(methoxy-d3)-4-H, HH, HH—SCF3—CD3,—H,((trifluoromethyl)thio)phenyl)-N-—CD3—CH2C3H5(cyclopropylmethyl)ethan-1-amineV-72-(2,5-bis(methoxy-d3)-4-D, DH, HH—SCF3—CD3,—H,((trifluoromethyl)thio)phenyl)-N-—CD3—CH2C3H5(cyclopropylmethyl)ethan-1,1-d2-1-amineV-82-(2,5-bis(methoxy-d3)-4-D, DD, DH—SCF3—CD3,—H,((trifluoromethyl)thio)phenyl)-N-—CD3—CH2C3H5(cyclopropylmethyl)ethan-1,1,2,2-d4-1-amineV-36N-(cyclopropylmethyl)-2-(4-H, HH, HH—SCF2H—Me,—H,((difluoromethyl)thio)-2,5-—Me—CH2C3H5dimethoxyphenyl)ethan-1-amineIn some embodiments, where R4 is —ORb or —SRb, Rb is not a substituted C2 alkyl group, e.g., a C2 fluoroalkyl group. In some embodiments, when X1, X2, Y1, Y2, R3, R6, and R7 are each hydrogen and each Ra is methyl, R4 is not —SCH2CH2CFH2, —SCH2C≡CH1—SCFH2, —SCF2H, or —SCF3. In some embodiments, R4 is not —SCH2CH2CFH2, for example when X1, X2, Y1, Y2, R3, R6, and R7 are each hydrogen and each Ra is methyl (e.g., in some embodiments the compound is not compound I-4). In some embodiments, R4 is not —SCH2C≡CH, for example when X1, X2, Y1, Y2, R3, R6, and R7 are each hydrogen and each Ra is methyl (e.g., in some embodiments the compound is not compound I-11). In some embodiments, R4 is not —SCFH2, for example when X1, X2, Y1, Y2, R3, R6, and R7 are each hydrogen and each Ra is methyl (e.g., in some embodiments the compound is not compound I-9). In some embodiments, R4 is not —SCF2H, for example when X1, X2, Y1, Y2, R3, R6, and R7 are each hydrogen and each Ra is methyl (e.g., in some embodiments the compound is not compound I-8). In some embodiments, R4 is not —SCF3, for example when X1, X2, Y1, Y2, R3, R6, and R7 are each hydrogen and each Ra is methyl (e.g., in some embodiments the compound is not compound I-1).Formula (VI)Disclosed herein is a compound according to Formula (VI):or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof,wherein:X1 and X2 are independently hydrogen or deuterium;Y1 and Y2 are independently hydrogen or deuterium;R3 is hydrogen or deuterium;R6 and R7 are independently hydrogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; or alternatively R6 and R7 together with the nitrogen atom attached thereto are optionally joined to form a substituted or unsubstituted heterocycloalkyl;

[0518] each Ra is independently a substituted or unsubstituted C1-C6 alkyl; and

[0519] each Rb is independently a substituted or unsubstituted C1-C2 alkyl; or alternatively two Rbs together with the carbon atom attached thereto are optionally joined to form a substituted or unsubstituted cycloalkyl.

[0520] X1 and X2 may be the same, or different. In some embodiments, X1 and X2 are the same. In some embodiments, X1 and X2 are hydrogen. In some embodiments, X1 and X2 are deuterium.

[0521] Y1 and Y2 may be the same, or different. In some embodiments, Y1 and Y2 are the same. In some embodiments, Y1 and Y2 are hydrogen. In some embodiments, Y1 and Y2 are deuterium.

[0522] In some embodiments, R3 is deuterium. In some embodiments, R3 is hydrogen.

[0523] R6 and R7 may be the same, or different. In some embodiments, R6 and R7 are the same. For example, in some embodiments, both R6 and R7 are hydrogen. In some embodiments, R6 and R7 are different. For example, in some embodiments, R6 is hydrogen, and R7 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0524] In some embodiments, R6 and / or R7 is an unsubstituted C1-C6 alkyl, for example, an unsubstituted C1 alkyl, an unsubstituted C2 alkyl, an unsubstituted C3 alkyl, an unsubstituted C4 alkyl, an unsubstituted C5 alkyl, or an unsubstituted C6 alkyl. In some embodiments, R6 and / or R7 is an unsubstituted linear C2-C6 alkyl. In some embodiments, R6 and / or R7 is an unsubstituted branched C3-C10 alkyl. Examples of an unsubstituted C1-C10 alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, and isohexyl.

[0525] In some embodiments, R6 and / or R7 is a substituted C1-C6 alkyl, e.g., a substituted C1 alkyl, a substituted C2 alkyl, a substituted C3 alkyl, a substituted C4 alkyl, a substituted C5 alkyl, or a substituted C6 alkyl. The alkyl group may contain one, or more than one, substituent. The alkyl group may be substituted with any one or more substituents recited herein, examples of those substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, oxo, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), unsubstituted alkenyl, substituted alkenyl, unsubstituted alkynyl, substituted alkynyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. In some embodiments, R6 and / or R7 is a C1-C6 alkyl substituted with one or more deuterium atoms, examples of which include, but are not limited to, —CDH2, —CD2H, —CD3, —CD2CD3, and —CD2CD2CD3. In some embodiments, R6 and / or R7 is a C1-C6 alkyl substituted with one or more fluorine atoms, i.e., is a fluoroalkyl group. Examples of fluoroalkyl groups include, but are not limited to, —CH2F, —CHF2, —CF3, —CH2CH2F, —CH2CHF2, —CH2CF3, —CH2CH2CH2F, —CH2CH2CHF2, —CH2CH2CF3, —CH2CH2CH2CH2F, —CH2CH2CH2CHF2, —CH2CH2CH2CF3, —CH2CF2CHF2, —CH2CF2CF3, —CH(CF3)2, and —CH(CH3)CF3.

[0526] In some embodiments, R6 and / or R7 is a C1-C6 alkyl substituted with one or more deuterium atoms and one or more fluorine atoms, examples of which include, but are not limited to, —CD2CH2F, —CD2CHF2, —CD2CF3, —CD2CH2CH2F, —CD2CH2CHF2, —CD2CH2CF3, —CD2CD2CH2, —CD2CD2CHF2, —CD2CD2CF3, —CD2CH2CH2CH2F, —CD2CH2CH2CHF2, —CD2CH2CH2CF3, —CD2CD2CH2CH2F, —CD2CD2CH2CHF2, —CD2CD2CH2CF3, —CD2CD2CD2CH2F, —CD2CD2CD2CHF2, and —CD2CD2CD2CF3.

[0527] In some embodiments, R6 and / or R7 is a C1-C6 alkyl substituted with a substituted or unsubstituted cycloalkyl. The C1-C6 alkyl may be substituted with, e.g., a substituted or unsubstituted C3-C10 cycloalkyl, or a substituted or unsubstituted C4-C8 cycloalkyl, or a substituted or unsubstituted C5-C6 cycloalkyl. In some embodiments, the C1-C6 alkyl is substituted with an unsubstituted cycloalkyl (e.g., an unsubstituted C3-C10 cycloalkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the C1-C6 alkyl is substituted with a substituted cycloalkyl (e.g., a substituted C3-C10 cycloalkyl). The cycloalkyl group may be substituted with any one or more substituents recited herein, examples of those substituents may include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The cycloalkyl group may contain one, or more than one, substituent. In some embodiments, R6 and / or R7 is a C1 alkyl substituted with a substituted or unsubstituted cycloalkyl, with particular mention being made to cyclopropylmethyl (—CH2C3H5).

[0528] In some embodiments, R6 and / or R7 is a substituted or unsubstituted alkenyl, e.g., a substituted or unsubstituted allyl, butenyl, crotyl, etc.

[0529] In some embodiments, R6 and / or R7 is a substituted or unsubstituted alkynyl, e.g., a substituted or unsubstituted propargyl.

[0530] In some embodiments, R6 and / or R7 is a substituted or unsubstituted cycloalkyl, for example a substituted or unsubstituted C3-C10 cycloalkyl, or a substituted or unsubstituted C4-C8 cycloalkyl, or a substituted or unsubstituted C5-C6 cycloalkyl. In some embodiments, R6 and / or R7 is an unsubstituted cycloalkyl (e.g., an unsubstituted C3-C10 cycloalkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, R6 and / or R7 is a substituted cycloalkyl (e.g., a substituted C3-C10 cycloalkyl). The cycloalkyl group may be substituted with any one or more substituents recited herein, examples of those substituents may include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The cycloalkyl group may contain one, or more than one, substituent.

[0531] In some embodiments, R6 and / or R7 is a substituted or unsubstituted heterocycloalkyl. In some embodiments, the unsubstituted or substituted heterocycloalkyl group may be a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, or an 8-membered ring. In some embodiments, R6 and / or R7 is an unsubstituted heterocycloalkyl, such as those set forth herein, examples of which include, but are not limited to, aziridine, azetidine, pyrrolidine, isoindole, indole, dihydroindole, indazole, purine, carbazole, carboline, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, thiazolidine, morpholine, thiomorpholine, tetrahydrofuran, tetrahydropyran, and 1,3-dioxolane. In some embodiments, R6 and / or R7 is a substituted heterocycloalkyl. The substituent(s) may be any recited herein, including, but not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), oxo, and hydroxyl. The heterocycloalkyl group may contain one, or more than one, substituent.

[0532] In some embodiments, R6 and / or R7 is a substituted or unsubstituted aryl. In some embodiments, R6 and / or R7 is an unsubstituted aryl, examples of which include, but are not limited to, phenyl and naphthyl. In some embodiments, R6 and / or R7 is a substituted aryl. The substituent(s) may be any recited herein, including, but not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The aryl group may contain one, or more than one, substituent.

[0533] In some embodiments, R6 and / or R7 is a substituted or unsubstituted heteroaryl. In some embodiments, R6 and / or R7 is an unsubstituted heteroaryl, examples of which include, but are not limited to, pyrrolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzofuranyl, benzothiophenyl, thiophenyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, and pyrazolyl. In some embodiments, R6 and / or R7 is a substituted heteroaryl. The substituent(s) may be any recited herein, including, but not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The heteroaryl group may contain one, or more than one, substituent.

[0534] In some embodiments, R6 is hydrogen, and R7 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. In some embodiments, R6 is hydrogen, and R7 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, R6 is hydrogen, and R7 is an unsubstituted C1-C6 alkyl, a C1-C6 alkyl substituted with one or more deuterium atoms, a C1-C6 alkyl substituted with one or more fluorine atoms, or a C1-C6 alkyl substituted with a substituted or unsubstituted cycloalkyl. For example, in some embodiments, R6 is hydrogen, and R7 is methyl, ethyl, propyl, —CD3, or cyclopropylmethyl (—CH2C3H5).

[0535] In some embodiments, R6 and R7 together with the nitrogen atom attached thereto are joined to form a substituted or unsubstituted heterocycloalkyl. In some embodiments, R6 and R7 together with the nitrogen atom attached thereto are joined to form an unsubstituted heterocycloalkyl. The unsubstituted heterocycloalkyl group may be, e.g., a 3-membered ring, a 4-membered ring, 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, etc., which may be optionally fused to other ring(s). The unsubstituted heterocycloalkyl group contains a minimum of one nitrogen ring atom (the nitrogen atom intervening R6 and R7), and may optionally contain at least one additional hetero-ring atom, which may be one or more of nitrogen, sulfur, or oxygen, for a total of 1, 2, 3, or 4 hetero-ring atoms (at least one of which is a nitrogen ring atom). Examples of unsubstituted heterocycloalkyl groups formed from joining R6 and R7 together with the nitrogen atom attached thereto include, but are not limited to,

[0536] In some embodiments, R6 and R7 together with the nitrogen atom attached thereto are joined to form a substituted heterocycloalkyl. The substituted heterocycloalkyl group may be, e.g., a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, etc., which may be optionally fused to other ring(s). The substituted heterocycloalkyl group contains a minimum of one nitrogen ring atom (the nitrogen atom intervening R6 and R7), and may optionally contain additional hetero-ring atoms (e.g., nitrogen, sulfur, or oxygen) for a total of 1, 2, 3, or 4 hetero-ring atoms (at least one of which is a nitrogen ring atom). Examples of the substituted heterocycloalkyl group include, but are not limited to, aziridine, azetidine, pyrrolidine, isoindole, indole, dihydroindole, indazole, purine, carbazole, carboline, imidazolidine, imidazoline, piperidine, piperazine, indoline, 1,2,3,4-tetrahydroisoquinoline, thiazolidine, morpholine, or thiomorpholine, which is substituted with at least one substituent. The substituent(s) may be any recited herein, including, but not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, oxo, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), unsubstituted alkyl, substituted alkyl, unsubstituted alkenyl, substituted alkenyl, unsubstituted alkynyl, substituted alkynyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The substituted heterocycloalkyl formed from joining R6 and R7 together with the nitrogen atom attached thereto contains a heterocycloalkyl group substituted with one, two, three, four, or more substituents. The substituent may be located on a carbon ring atom or on a hetero-ring atom.

[0537] Examples of substituted heterocycloalkyl groups formed from joining R6 and R7 together with the nitrogen atom attached thereto include, but are not limited to,

[0538] Each Ra may be the same, or different. In some embodiments, each Ra is the same. Each Ra may be, independently, a substituted or unsubstituted C1-C6 alkyl, preferably a substituted or unsubstituted C1-C3 alkyl, preferably a substituted or unsubstituted C1 alkyl, examples of which include, but are not limited to, —CH3, —CDH2, —CD2H, —CD3, —CFH2, —CF2H, —CF3. In some embodiments, each Ra is —CH3. In some embodiments, each Ra is —CD3. In some embodiments, each Ra is different, e.g., one Ra is —CH3, while another is —CD3.

[0539] Each Rb may be the same, or different. In some embodiments, each Rb is the same. Each Rb may be, independently, a substituted or unsubstituted C1-C2 alkyl, preferably a substituted or unsubstituted C1 alkyl, examples of which include, but are not limited to, —CH3, —CDH2, —CD2H, —CD3, —CFH2, —CF2H, —CF3. In some embodiments, each Rb is selected from the group consisting of —CDH2, —CD2H, —CD3, and —CH3. In some embodiments, each Rb is—CH3. In some embodiments, each Rb is —CD3. In some embodiments, at least one Rb is different from the others, e.g., one Rb is —CH2CH3, while the other two are —CH3. In some embodiments, one Rb is —CF3, while the other two are —CH3. In some embodiments, one Rb is —CH3, while the other two are —CF3.

[0540] In some embodiments, two Rbs together with the carbon atom attached thereto are joined to form a substituted or unsubstituted cycloalkyl group. In some embodiments, the substituted or unsubstituted cycloalkyl group formed from joining two Rbs, together with the carbon atom attached thereto, may be for example a substituted or unsubstituted C3-C10 cycloalkyl, or a substituted or unsubstituted C4-C8 cycloalkyl, or a substituted or unsubstituted C5-C6 cycloalkyl. In some embodiments, two Rbs, together with the carbon atom attached thereto, are joined to form an unsubstituted cycloalkyl (e.g., an unsubstituted C3-C10 cycloalkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, two Rbs, together with the carbon atom attached thereto, are joined to form a substituted cycloalkyl (e.g., a substituted C3-C10 cycloalkyl). The cycloalkyl group may be substituted with any one or more substituents recited herein, examples of those substituents may include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The cycloalkyl group may contain one, or more than one, substituent. When two Rbs together with the carbon atom attached thereto are joined to form a substituted or unsubstituted cycloalkyl group, the remaining Rb is selected as set forth above, e.g., —CH3, —CDH2, —CD2H, —CD3, —CFH2, —CF2H, or —CF3.

[0541] In some embodiments, Y1 and Y2 are each hydrogen or each deuterium; R3 is hydrogen; X1 and X2 are each hydrogen or each deuterium; each Ra is —CH3 or —CD3; and each Rb is —CD3, or —CH3.

[0542] In some embodiments, the compound, e.g., the compound of Formula (VI) is selected from the group consisting of:or a pharmaceutically acceptable salt, solvate, or prodrug thereof.The compounds of Formula (VI) containing a quaternary carbon atom attached to the 4-position of the phenyl ring, in particular a lipophilic tertiary alkyl group in the 4-position of the phenyl ring (e.g., a t-butyl group) have been found to possess a surprisingly strong binding affinity to 5-HT2 receptors such as 5-HT2A, especially when compared to compounds lacking a quaternary carbon at the same position, such as the case in cyclopentyl groups. In addition to their excellent pharmacodynamic properties, the compounds of Formula (VI), bearing a quaternary carbon atom attached to the 4-position of the phenyl ring, may also provide advantageous pharmacokinetics by slowing or shunting metabolism at this position, for improved bioavailability, exposure, and brain penetrability.Formula (VII)

[0544] Disclosed herein is a compound according to Formula (VII):or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof,

[0546] wherein:

[0547] X1 and X2 are independently hydrogen or deuterium;

[0548] Y1 and Y2 are independently hydrogen or deuterium;

[0549] R6 is hydrogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl;

[0550] R7 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl;

[0551] or alternatively R6 and R7 together with the nitrogen atom attached thereto are optionally joined to form a substituted or unsubstituted heterocycloalkyl;

[0552] each Ra is independently a substituted or unsubstituted C1-C6 alkyl; and

[0553] Rb is hydrogen, deuterium, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, or a substituted or unsubstituted C3-C10 cycloalkyl.

[0554] X1 and X2 may be the same, or different. In some embodiments, X1 and X2 are the same. In some embodiments, X1 and X2 are hydrogen. In some embodiments, X1 and X2 are deuterium.

[0555] Y1 and Y2 may be the same, or different. In some embodiments, Y1 and Y2 are the same. In some embodiments, Y1 and Y2 are hydrogen. In some embodiments, Y1 and Y2 are deuterium.

[0556] In some embodiments, Rb is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, Rb is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. In some embodiments, Rb is a substituted C1-C6 alkyl. Preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), cyano, polar substituents such as hydroxyl or polyether substituents, etc. The C1-C6 alkyl group may contain one, or more than one, substituent. In some embodiments, Rb is a substituted C1 alkyl group, examples of which may include, but are not limited to, —CDH2, —CD2H, —CD3, —CFH2, —CF2H, —CF3, and —CH2C≡N. In some embodiments, Rb is a substituted C2 alkyl group, examples of which may include, but are not limited to, —CDHCDH2, —CDHCD2H, —CD2CD3, —CH2CFH2, —CH2CF2H, —CH2CF3, and —CH2CH2C≡N. In some embodiments, Rb is not a substituted C2 alkyl group such as a C2 fluoroalkyl group. For example, in some embodiments when R4 is —ORb or —SRb, Rb is not —CH2CFH2, —CH2CF2H, or —CH2CF3. In some embodiments, Rb is a substituted C3 alkyl group, examples of which may include, but are not limited to —CH2CH2CF3, —CH2CH2CF2H, —CH2CH2CFH2, —CH2CF2CF2H, and —CH2CH2CH2C≡N. In some embodiments, Rb is not —CH2CH2CFH2.

[0557] In some embodiments, Rb is a substituted or unsubstituted alkenyl, e.g., a substituted or unsubstituted allyl, butenyl, crotyl, etc.

[0558] In some embodiments, Rb is a substituted or unsubstituted alkynyl, e.g., a substituted or unsubstituted acetylenyl, propargyl, homopropargyl, etc. In some embodiments, Rb is an unsubstituted alkynyl. In some embodiments, Rb is an unsubstituted acetylenyl (—C≡CH). In some embodiments, Rb is an unsubstituted propargyl (—CH2C≡CH). In some embodiments, Rb is —CH2CH2C≡CH. In some embodiments, Rb is —CH2CH2CH2C≡CH. In some embodiments, Rb is —CH2CH2CH2CH2C≡CH. In some embodiments, Rb is a substituted alkynyl. In some embodiments, Rb is a substituted propargyl (e.g., —CF2C≡CH). In some embodiments, Rb is —CF2CH2C≡CH. In some embodiments, Rb is —CF2CH2CH2C≡CH. In some embodiments, Rb is —CF2CH2CH2CH2C≡CH.

[0559] In some embodiments, Rb is a substituted or unsubstituted cycloalkyl, for example a substituted or unsubstituted C3-C10 cycloalkyl, or a substituted or unsubstituted C4-C8 cycloalkyl, or a substituted or unsubstituted C5-C6 cycloalkyl. In some embodiments, Rb is an unsubstituted cycloalkyl (e.g., an unsubstituted C3-C10 cycloalkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, Rb is a substituted cycloalkyl (e.g., a substituted C3-C10 cycloalkyl). The cycloalkyl group may be substituted with any one or more substituents recited herein, examples of those substituents may include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The cycloalkyl group may contain one, or more than one, substituent.

[0560] In some embodiments, Rb is —C≡CH, —CH2C≡N, —CH2C≡CH, —CF2C≡CH, —CH2CH2C≡CH, —CF2CH2C≡CH, —CH2CH2CH2C≡CH, —CF2CH2CH2C≡CH, —CH2CH2CH2CH2C≡CH, and —CF2CH2CH2CH2C≡CH. R6 and R7 may be the same, or different. In some embodiments, R6 and R7 are the same. In some embodiments, R6 and R7 are different. For example, in some embodiments, R6 is hydrogen, and R7 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0561] In some embodiments, R6 and / or R7 is an unsubstituted C1-C6 alkyl, for example, an unsubstituted C1 alkyl, an unsubstituted C2 alkyl, an unsubstituted C3 alkyl, an unsubstituted C4 alkyl, an unsubstituted C5 alkyl, or an unsubstituted C6 alkyl. In some embodiments, R6 and / or R7 is an unsubstituted linear C2-C6 alkyl. In some embodiments, R6 and / or R7 is an unsubstituted branched C3-C10 alkyl. Examples of an unsubstituted C1-C10 alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, and isohexyl.

[0562] In some embodiments, R6 and / or R7 is a substituted C1-C6 alkyl, e.g., a substituted C1 alkyl, a substituted C2 alkyl, a substituted C3 alkyl, a substituted C4 alkyl, a substituted C5 alkyl, or a substituted C6 alkyl. The alkyl group may contain one, or more than one, substituent. The alkyl group may be substituted with any one or more substituents recited herein, examples of those substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, oxo, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), unsubstituted alkenyl, substituted alkenyl, unsubstituted alkynyl, substituted alkynyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. In some embodiments, R6 and / or R7 is a C1-C6 alkyl substituted with one or more deuterium atoms, examples of which include, but are not limited to, —CDH2, —CD2H, —CD3, —CD2CD3, and —CD2CD2CD3. In some embodiments, R6 and / or R7 is a C1-C6 alkyl substituted with one or more fluorine atoms, i.e., is a fluoroalkyl group. Examples of fluoroalkyl groups include, but are not limited to, —CH2F, —CHF2, —CF3, —CH2CH2F, —CH2CHF2, —CH2CF3, —CH2CH2CH2F, —CH2CH2CHF2, —CH2CH2CF3, —CH2CH2CH2CH2F, —CH2CH2CH2CHF2, —CH2CH2CH2CF3, —CH2CF2CHF2, —CH2CF2CF3, —CH(CF3)2, and —CH(CH3)CF3.

[0563] In some embodiments, R6 and / or R7 is a C1-C6 alkyl substituted with one or more deuterium atoms and one or more fluorine atoms, examples of which include, but are not limited to, —CD2CH2F, —CD2CHF2, —CD2CF3, —CD2CH2CH2F, —CD2CH2CHF2, —CD2CH2CF3, —CD2CD2CH2, —CD2CD2CHF2, —CD2CD2CF3, —CD2CH2CH2CH2F, —CD2CH2CH2CHF2, —CD2CH2CH2CF3, —CD2CD2CH2CH2F, —CD2CD2CH2CHF2, —CD2CD2CH2CF3, —CD2CD2CD2CH2F, —CD2CD2CD2CHF2, and —CD2CD2CD2CF3.

[0564] In some embodiments, R6 and / or R7 is a C1-C6 alkyl substituted with a substituted or unsubstituted cycloalkyl. The C1-C6 alkyl may be substituted with, e.g., a substituted or unsubstituted C3-C10 cycloalkyl, or a substituted or unsubstituted C4-C8 cycloalkyl, or a substituted or unsubstituted C5-C6 cycloalkyl. In some embodiments, the C1-C6 alkyl is substituted with an unsubstituted cycloalkyl (e.g., an unsubstituted C3-C10 cycloalkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the C1-C6 alkyl is substituted with a substituted cycloalkyl (e.g., a substituted C3-C10 cycloalkyl). The cycloalkyl group may be substituted with any one or more substituents recited herein, examples of those substituents may include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The cycloalkyl group may contain one, or more than one, substituent. In some embodiments, R6 and / or R7 is a C1 alkyl substituted with a substituted or unsubstituted cycloalkyl, with particular mention being made to cyclopropylmethyl (—CH2C3H5).

[0565] In some embodiments, R6 and / or R7 is a substituted or unsubstituted alkenyl, e.g., a substituted or unsubstituted allyl, butenyl, crotyl, etc.

[0566] In some embodiments, R6 and / or R7 is a substituted or unsubstituted alkynyl, e.g., a substituted or unsubstituted propargyl.

[0567] In some embodiments, R6 and / or R7 is a substituted or unsubstituted cycloalkyl, for example a substituted or unsubstituted C3-C10 cycloalkyl, or a substituted or unsubstituted C4-C8 cycloalkyl, or a substituted or unsubstituted C5-C6 cycloalkyl. In some embodiments, R6 and / or R7 is an unsubstituted cycloalkyl (e.g., an unsubstituted C3-C10 cycloalkyl), examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, R6 and / or R7 is a substituted cycloalkyl (e.g., a substituted C3-C10 cycloalkyl). The cycloalkyl group may be substituted with any one or more substituents recited herein, examples of those substituents may include, but are not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, oxo, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The cycloalkyl group may contain one, or more than one, substituent.

[0568] In some embodiments, R6 and / or R7 is a substituted or unsubstituted heterocycloalkyl. In some embodiments, the unsubstituted or substituted heterocycloalkyl group may be a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, or an 8-membered ring. In some embodiments, R6 and / or R7 is an unsubstituted heterocycloalkyl, such as those set forth herein, examples of which include, but are not limited to, aziridine, azetidine, pyrrolidine, isoindole, indole, dihydroindole, indazole, purine, carbazole, carboline, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, thiazolidine, morpholine, thiomorpholine, tetrahydrofuran, tetrahydropyran, and 1,3-dioxolane. In some embodiments, R6 and / or R7 is a substituted heterocycloalkyl. The substituent(s) may be any recited herein, including, but not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), oxo, and hydroxyl. The heterocycloalkyl group may contain one, or more than one, substituent.

[0569] In some embodiments, R6 and / or R7 is a substituted or unsubstituted aryl. In some embodiments, R6 and / or R7 is an unsubstituted aryl, examples of which include, but are not limited to, phenyl and naphthyl. In some embodiments, R6 and / or R7 is a substituted aryl. The substituent(s) may be any recited herein, including, but not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The aryl group may contain one, or more than one, substituent.

[0570] In some embodiments, R6 and / or R7 is a substituted or unsubstituted heteroaryl. In some embodiments, R6 and / or R7 is an unsubstituted heteroaryl, examples of which include, but are not limited to, pyrrolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzofuranyl, benzothiophenyl, thiophenyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, and pyrazolyl. In some embodiments, R6 and / or R7 is a substituted heteroaryl. The substituent(s) may be any recited herein, including, but not limited to, deuterium, unsubstituted alkyl, substituted alkyl, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), halogen (e.g., fluorine), hydroxyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The heteroaryl group may contain one, or more than one, substituent.

[0571] In some embodiments, R6 is hydrogen, and R7 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. In some embodiments, R6 is hydrogen, and R7 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, R6 is hydrogen, and R7 is an unsubstituted C1-C6 alkyl, a C1-C6 alkyl substituted with one or more deuterium atoms, a C1-C6 alkyl substituted with one or more fluorine atoms, or a C1-C6 alkyl substituted with a substituted or unsubstituted cycloalkyl. For example, in some embodiments, R6 is hydrogen, and R7 is methyl, ethyl, propyl, —CD3, or cyclopropylmethyl (—CH2C3H5).

[0572] In some embodiments, R6 and R7 together with the nitrogen atom attached thereto are joined to form a substituted or unsubstituted heterocycloalkyl. In some embodiments, R6 and R7 together with the nitrogen atom attached thereto are joined to form an unsubstituted heterocycloalkyl. The unsubstituted heterocycloalkyl group may be, e.g., a 3-membered ring, a 4-membered ring, 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, etc., which may be optionally fused to other ring(s). The unsubstituted heterocycloalkyl group contains a minimum of one nitrogen ring atom (the nitrogen atom intervening R6 and R7), and may optionally contain at least one additional hetero-ring atom, which may be one or more of nitrogen, sulfur, or oxygen, for a total of 1, 2, 3, or 4 hetero-ring atoms (at least one of which is a nitrogen ring atom). Examples of unsubstituted heterocycloalkyl groups formed from joining R6 and R7 together with the nitrogen atom attached thereto include, but are not limited to,

[0573] In some embodiments, R6 and R7 together with the nitrogen atom attached thereto are joined to form a substituted heterocycloalkyl. The substituted heterocycloalkyl group may be, e.g., a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, etc., which may be optionally fused to other ring(s). The substituted heterocycloalkyl group contains a minimum of one nitrogen ring atom (the nitrogen atom intervening R6 and R7), and may optionally contain additional hetero-ring atoms (e.g., nitrogen, sulfur, or oxygen) for a total of 1, 2, 3, or 4 hetero-ring atoms (at least one of which is a nitrogen ring atom). Examples of the substituted heterocycloalkyl group include, but are not limited to, aziridine, azetidine, pyrrolidine, isoindole, indole, dihydroindole, indazole, purine, carbazole, carboline, imidazolidine, imidazoline, piperidine, piperazine, indoline, 1,2,3,4-tetrahydroisoquinoline, thiazolidine, morpholine, or thiomorpholine, which is substituted with at least one substituent. The substituent(s) may be any recited herein, including, but not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, oxo, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), unsubstituted alkyl, substituted alkyl, unsubstituted alkenyl, substituted alkenyl, unsubstituted alkynyl, substituted alkynyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl. The substituted heterocycloalkyl formed from joining R6 and R7 together with the nitrogen atom attached thereto contains a heterocycloalkyl group substituted with one, two, three, four, or more substituents. The substituent may be located on a carbon ring atom or on a hetero-ring atom.

[0574] Examples of substituted heterocycloalkyl groups formed from joining R6 and R7 together with the nitrogen atom attached thereto include, but are not limited to,

[0575] Each Ra may be the same, or different. In some embodiments, each Ra is the same. Each Ra may be, independently, a substituted or unsubstituted C1-C6 alkyl, preferably a substituted or unsubstituted C1-C3 alkyl, preferably a substituted or unsubstituted C1 alkyl, examples of which include, but are not limited to, —CH3, —CDH2, —CD2H, —CD3, —CFH2, —CF2H, —CF3. In some embodiments, each Ra is —CH3. In some embodiments, each Ra is —CD3. In some embodiments, each Ra is different, e.g., one Ra is —CH3, while another is —CD3.

[0576] In some embodiments, the compound, e.g., the compound of Formula (VII) is selected from the group consisting ofor a pharmaceutically acceptable salt, solvate, or prodrug thereof.The compounds of Formula (I) through (VII) may contain a stereogenic center. In such cases, the compounds may exist as different stereoisomeric forms, even though Formula (I) through (VII) are drawn without reference to stereochemistry. Accordingly, the present disclosure includes all possible stereoisomers and includes not only racemic compounds but the individual enantiomers (enantiomerically pure compounds) and their non-racemic mixtures as well. When a compound is desired as a single enantiomer, such may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as each are known in the art. Resolution of the final product, an intermediate, or a starting material may be performed by any suitable method known in the art.In some embodiments, the compounds described herein, e.g., compounds of Formula (I) through (VII), are racemic. In some embodiments, the compounds described herein, e.g., compounds of Formula (I) through (VII), are enantiomerically pure.

[0579] In some embodiments, the compound is an agonist of a serotonin 5-HT2 receptor. In some embodiments, the compound is an agonist of a serotonin 5-HT2A receptor. In some embodiments, the compound is an agonist of a serotonin 5-HT1A receptor. In some embodiments, the compound is an agonist of a serotonin 5-HT2C receptor. In some embodiments, administration of the compound elicits psychedelic effects. In some embodiments, administration of the compound does not elicit psychedelic effects (e.g., at dosages that would classically produce psychedelic effects).

[0580] Also disclosed herein is a pharmaceutically acceptable salt of the compounds of the present disclosure, e.g., a compound of Formula (I) through (VII). The acid used to form the pharmaceutically acceptable salt of the compound of Formula (I) through (VII) may be a monoacid, a diacid, a triacid, a tetraacid, or may contain a higher number of acid groups. The acid groups may be, e.g., a carboxylic acid, a sulfonic acid, a phosphonic acid, or other acidic moieties containing at least one replaceable hydrogen atom. Examples of acids for use in the preparation of the pharmaceutically acceptable (acid addition) salts disclosed herein include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, phenylacetic acid, acylated amino acids, alginic acid, ascorbic acid, L-aspartic acid, sulfonic acids (e.g., benzenesulfonic acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, p-toluenesulfonic acid, ethanedisulfonic acid, etc.), benzoic acids (e.g., benzoic acid, 4-acetamidobenzoic acid, 2-acetoxybenzoic acid, salicylic acid, 4-amino-salicylic acid, gentisic acid, etc.), boric acid, (+)-camphoric acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, formic acid, fumaric acid, galactaric acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (−)-D-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, malic acid, (−)-L-malic acid, (+)-D-malic acid, hydroxymaleic acid, malonic acid, (±)-DL-mandelic acid, isethionic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, orotic acid, oxalic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, succinic acid, sulfuric acid, sulfamic acid, tannic acid, tartaric acids (e.g., DL-tartaric acid, (+)-L-tartaric acid, (−)-D-tartaric acid), thiocyanic acid, propionic acid, valeric acid, and fatty acids (including fatty mono- and di-acids, e.g., adipic (hexandioic) acid, lauric (dodecanoic) acid, linoleic acid, myristic (tetradecanoic) acid, capric (decanoic) acid, stearic (octadecanoic) acid, oleic acid, caprylic (octanoic) acid, palmitic (hexadecenoic) acid, sebacic acid, undecylenic acid, caproic acid, etc.).

[0581] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) through (VII) is a benzenesulfonate salt, a tartrate salt, a hemi-fumarate salt, an acetate salt, a citrate salt, a malonate salt, a fumarate salt, a succinate salt, an oxalate salt, a benzoate salt, a salicylate salt, an ascorbate salt, a hydrochloride salt, a maleate salt, a malate salt, a methanesulfonate salt, a toluenesulfonate salt, a glucuronate salt, or a glutarate salt of the compound of Formula (I) through (VII). In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) through (VII) is a salt formed from a sulfonic acid (e.g., benzenesulfonic acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, p-toluenesulfonic acid, ethanedisulfonic acid, etc.). In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) through (VII) is a salt formed from a benzoic acid (e.g., benzoic acid, 4-acetamidobenzoic acid, 2-acetoxybenzoic acid, salicylic acid, 4-amino-salicylic acid, etc.).

[0582] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) through (VII) is a fatty acid salt. The fatty acid used to make the fatty acid salt of the compound of Formula (I) through (VII) may be a fatty monoacid or a fatty diacid, and may contain a fatty hydrocarbon portion made up of hydrogen and anywhere from 4, from 6, from 8, from 10, from 12, from 14, from 16, and up to 26, up to 24, up to 22, up to 20, up to 18 carbon atoms, which may be fully saturated or partially unsaturated. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) through (VII) is an adipate salt, a laurate salt, a linoleate salt, a myristate salt, a caprate salt, a stearate salt, an oleate salt, a caprylate salt, a palmitate salt, a sebacate salt, an undecylenate salt, or a caproate salt of the compound of Formula (I) through (VII).

[0583] Methods for preparing pharmaceutically acceptable salt forms of pharmaceutical compounds are known by those of ordinary skill in the art. In some embodiments, the method includes:

[0584] (a) suspending the compound of Formula (I) through (VII) in a solvent or mixture of solvents;

[0585] (b) contacting an acid with the compound of Formula (I) through (VII) to provide a mixture;

[0586] (c) optionally heating the mixture;

[0587] (d) optionally cooling the mixture; and

[0588] (e) isolating the salt.

[0589] Various solvents may be used in the disclosed methods, including one or more protic solvents, one or more aprotic solvents, or mixtures thereof. In some embodiments, the solvent(s) used in the method of preparing the salt is / are a protic solvent(s). In some embodiments, the solvent used in the method of preparing the salt is selected from the group consisting of methanol, ethanol, propanol, isopropanol (IPA), butanol, 2-butanol, acetone, butanone, dioxanes (1,4-dioxane), water, tetrahydrofuran (THF), acetonitrile (MeCN), ether solvents (e.g., t-butylmethyl ether (TBME)), hexane, heptane, octane, and combinations thereof. In some embodiments, the solvent is ethanol. In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is tetrahydrofuran.

[0590] Suitable acids for use in the preparation of pharmaceutically acceptable acid addition salts may include those described heretofore. The acid may be an inorganic acid such as hydrochloric acid, or an organic acid, with organic acids being preferred. In some embodiments, the acid is an organic acid selected from the group consisting of ascorbic acid, citric acid, fumaric acid, maleic acid, malonic acid, (−)-L-malic acid, (+)-L-tartaric acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, benzoic acid, salicylic acid, succinic acid, oxalic acid, D-glucuronic acid, glutaric acid salt, and acetic acid. In some embodiments, the acid is an organic acid selected from the group consisting of benzenesulfonic acid, (+)-L-tartaric acid, fumaric acid, acetic acid, citric acid, malonic acid, succinic acid, oxalic acid, benzoic acid, and salicylic acid. In some embodiments, the acid is a fatty acid, such as adipic (hexandioic) acid, lauric (dodecanoic) acid, linoleic acid, myristic (tetradecanoic) acid, capric (decanoic) acid, stearic (octadecanoic) acid, oleic acid, caprylic (octanoic) acid, palmitic (hexadecenoic) acid, sebacic acid, undecylenic acid, caproic acid, etc., with particular mention being made to adipic (hexandioic) acid, lauric (dodecanoic) acid, linoleic acid, myristic (tetradecanoic) acid, capric (decanoic) acid, stearic (octadecanoic) acid, oleic acid, and caprylic (octanoic) acid.

[0591] In some embodiments, a stoichiometric (or superstoichiometric) quantity of the acid is contacted with the compound of Formula (I) through (VII). In some embodiments, a sub-stoichiometric (e.g., 0.5 molar equivalents) quantity of the acid is contacted with the compound of Formula (I) through (VII). The use of sub-stoichiometric quantities of the acid may be desirable when, for example, the acid contains at least two acidic protons (e.g., two or more carboxylic acid groups) and the target salt is a hemi-acid salt.

[0592] In some embodiments, the mixture is heated, e.g., refluxed, prior to cooling.

[0593] In some embodiments, the mixture is cooled and the salt is precipitated out of the solution. In some embodiments, the salt is precipitated out of solution in crystalline form. In some embodiments, the salt is precipitated out of solution in amorphous form.

[0594] Isolation of the salt may be performed by various well-known isolation techniques, such as filtration, decantation, and the like. In some embodiments, the isolating step includes filtering the mixture.

[0595] After isolation, additional crystallization and / or recrystallization steps may also optionally be performed, if desired, for example to increase purity, crystallinity, etc.

[0596] In some embodiments, compounds of the present disclosure, e.g., a compound of Formula (I) through (VII), or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, is in the form of a solvate. Examples of solvate forms include, but are not limited to, hydrates, methanolates, ethanolates, isopropanolates, etc., with hydrates and ethanolates being preferred. The solvate may be formed from stoichiometric or nonstoichiometric quantities of solvent molecules. Solvates of the compounds herein may be in the form of isolable solvates. In one non-limiting example, as a hydrate, the compound may be a monohydrate, a dihydrate, etc. Solvates of the compounds herein also include solution-phase forms. Thus, in some embodiments, the present disclosure provides solution-phase compositions of the compounds of the present disclosure, or any pharmaceutically acceptable salts thereof, which are in solvated form, preferably fully solvated form.

[0597] In some embodiments, the compound of the present disclosure, e.g., a compound of Formula (I) through (VII), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is provided in crystalline form, e.g., as determined by XRPD. Accordingly, pharmaceutical compositions may be prepared from a compound of Formula (I) through (VII), in crystalline form including in one or more polymorphic forms, and may be used for treatment as set forth herein. Crystalline forms may be advantageous in terms of stability and providing well-defined physical properties, which is desirable for pharmaceutical preparation and administration.

[0598] In some embodiments, the compound of the present disclosure, e.g., a compound of Formula (I) through (VII), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is provided in amorphous form, e.g., as determined by XRPD. Accordingly, pharmaceutical compositions may be prepared from a compound of Formula (I) through (VII), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, in one or more amorphic forms, and may be used for treatment as set forth herein. Amorphous forms typically possess higher aqueous solubility and rates of dissolution compared to their crystalline counterparts, and thus may be well suited for quick acting dosage forms adapted to rapidly release the active agent, such as for orodispersible dosage forms (ODxs), immediate release (IR) dosage forms, and the like.

[0599] Compounds of the present disclosure, e.g., a compound of Formula (I) through (VII), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, may generally be prepared according to, or analogous to, the synthetic routes exemplified herein. Other synthetic routes may also be used according to techniques and procedures known to those of ordinary skill in the art.Therapeutic Applications and Methods

[0600] Also disclosed herein is a method of treating a subject with a disease or disorder comprising administering to the subject a therapeutically effective amount of a compound as disclosed herein (e.g., a compound of Formula (I) through (VII), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof). In some embodiments, the disease or disorder is associated with a serotonin 5-HT2 receptor.

[0601] The dosage and frequency (single or multiple doses) of the compounds administered herein can vary depending upon a variety of factors, including, but not limited to, the compound to be administered; the disease / condition being treated; route of administration; size, age, sex, health, body weight, body mass index, and diet of the subject; nature and extent of symptoms of the disease being treated; presence of other diseases or other health-related problems; kind of concurrent treatment; and complications from any disease or treatment regimen. Other therapeutic regimens or agents can be used in conjunction with the methods and compounds disclosed herein.

[0602] Therapeutically effective amounts for use in humans may be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring response to the treatment and adjusting the dosage upwards (e.g., up-titration) or downwards (e.g., down-titration).

[0603] Dosages may be varied depending upon the requirements of the subject and the active ingredient (e.g., a compound of Formula (I) through (VII), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof) being employed. The dose administered to a subject, in the context of the pharmaceutical compositions presented herein, should be sufficient to affect a beneficial therapeutic response in the subject over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side effects. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the active ingredient. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached.

[0604] Dosage amounts and intervals can be adjusted individually to provide levels of the administered compounds effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.

[0605] Routes of administration may include oral routes (e.g., enteral / gastric delivery, intraoral administration such buccal, lingual, and sublingual routes), parenteral routes (e.g., intravenous, intradermal, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration), topical routes (e.g., conjuctival, intracorneal, intraocular, ophthalmic, auricular, transdermal, nasal (e.g., intranasal), vaginal, uretheral, respiratory, and rectal administration), inhalation, or others sufficient to affect a beneficial therapeutic response.

[0606] Administration may follow a continuous administration schedule, or an intermittent administration schedule. The administration schedule may be varied depending on the active ingredient(s) employed, the condition being treated, the administration route, etc. For example, administration of a compound of Formula (I) through (VII), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, may be performed once a day (QD), or in divided dosages throughout the day, such as 2-times a day (BID), 3-times a day (TID), 4-times a day (QID), or more. In some embodiments administration may be performed nightly (QHS). In some embodiments, administration is performed as needed (PRN). Administration may also be performed on a weekly basis, e.g., once a week, twice a week, three times a week, four times a week, every other week, every two weeks, etc., or less. The administration schedule may also designate a defined number of treatments per treatment course, for example, the compound of Formula (I) through (VII), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, may be administered 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, or 8 times per treatment course. Other administration schedules may also be deemed appropriate using sound medical judgement.

[0607] The dosing can be continuous (7 days of administration in a week) or intermittent, for example, depending on the pharmacokinetics and a particular subject's clearance / accumulation of the drug. If intermittently, the schedule may be, for example, 4 days of administration and 3 days off (rest days) in a week or any other intermittent dosing schedule deemed appropriate using sound medical judgement. For example, intermittent dosing may involve administration of a single dose within a treatment course. The dosing whether continuous or intermittent is continued for a particular treatment course, typically at least a 28-day cycle (1 month), which can be repeated with or without a drug holiday. Longer or shorter courses can also be used such as 14 days, 18 days, 21 days, 24 days, 35 days, 42 days, 48 days, or longer, or any range therebetween. The course may be repeated without a drug holiday or with a drug holiday depending upon the subject. Other schedules are possible depending upon the presence or absence of adverse events, response to the treatment, patient convenience, and the like.

[0608] Utilizing the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity or adverse side effects (e.g., caused by sedative or psychotomimetic toxic spikes in plasma concentration of any of the compounds Formula (I) through (VII)), and yet is entirely effective to treat the clinical symptoms demonstrated by the particular patient. This planning should involve the careful choice of active ingredient by considering factors such as compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration, and the toxicity profile of the selected agent.

[0609] A therapeutically effective dose of the compounds of the present disclosure may vary depending on the variety of factors described above, but is typically that which provides the compound of Formula (I) through (VII) in an amount of about 0.00001 mg to about 10 mg per kilogram body weight of the subject, or any range in between, e.g., about 0.00001 mg / kg, about 0.00005 mg / kg, about 0.0001 mg / kg, about 0.0005 mg / kg, about 0.001 mg / kg, about 0.005 mg / kg, about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1.0 mg / kg, about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0 mg / kg, about 7.0 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10.0 mg / kg of the compound of Formula (I) through (VII) (on an active basis).

[0610] The compounds of the present disclosure (e.g., a compound of Formula (I) through (VII), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof) may be administered at a psychedelic dose. Psychedelic dosing, by mouth or otherwise, may in some embodiments range from about 0.3 mg / kg, about 0.35 mg / kg, about 0.4 mg / kg, about 0.45 mg / kg, about 0.5 mg / kg, and up to about 5 mg / kg, about 4 mg / kg, about 3 mg / kg, about 2 mg / kg, about 1 mg / kg, about 0.95 mg / kg, about 0.9 mg / kg, about 0.85 mg / kg, about 0.8 mg / kg, about 0.75 mg / kg, about 0.7 mg / kg, about 0.65 mg / kg, about 0.6 mg / kg, about 0.55 mg / kg of the compound of Formula (I) through (VII) (on an active basis). Higher dosing may also be used in some embodiments, as described above. In some embodiments, psychedelic doses are administered once by mouth or otherwise, with the possibility of repeat doses at least one week apart. In some instances, no more than 5 doses are given in any one course of treatment. Courses can be repeated as necessary, with or without a drug holiday. Such acute treatment regimens may be accompanied by psychotherapy, before, during, and / or after the psychedelic dose. These treatments are appropriate for a variety of mental health disorders disclosed herein, examples of which include, but are not limited to, major depressive disorder (MDD), therapy resistant depression (TRD), anxiety disorders, and substance use disorders (e.g., alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, smoking, and cocaine use disorder).

[0611] The compounds of the present disclosure (e.g., a compound of Formula (I) through (VII), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof), may be administered at sub-psychoactive (yet still potentially serotonergic concentrations) concentrations to achieve durable therapeutic benefits, with decreased toxicity, and may thus be suitable for microdosing. Sub-psychedelic dosing, by mouth or otherwise, may in some embodiments range from about 0.00001 mg / kg, about 0.00005 mg / kg, about 0.0001 mg / kg, about 0.0005 mg / kg, about 0.001 mg / kg, about 0.005 mg / kg, about 0.006 mg / kg, about 0.008 mg / kg, about 0.009 mg / kg, about 0.01 mg / kg, and up to about 0.3 mg / kg, about 0.25 mg / kg, about 0.2 mg / kg, about 0.15 mg / kg, about 0.1 mg / kg, about 0.083 mg / kg, about 0.08 mg / kg, about 0.075 mg / kg, about 0.07 mg / kg, about 0.06 mg / kg, about 0.05 mg / kg, about 0.04 mg / kg, about 0.03 mg / kg, about 0.02 mg / kg of the compound of Formula (I) through (VII) (on an active basis). Typically, sub-psychedelic doses are administered orally up to every day, for a treatment course (e.g., 1 month). However, there is no limitation on the number of doses at sub-psychedelic doses-dosing can be less frequent or more frequent as deemed appropriate. Courses can be repeated as necessary, with or without a drug holiday.

[0612] Sub-psychedelic dosing can also be carried out, for example, by transdermal delivery, subcutaneous administration, etc., via modified, controlled, slow, or extended release dosage forms, including, but not limited to, depot dosage forms, implants, patches, and pumps, which can be optionally remotely controlled. Here, doses would achieve similar blood levels as low oral dosing, but would nevertheless be sub-psychedelic.

[0613] Sub-psychedelic doses can be used, e.g., for the chronic treatment or maintenance of a variety of diseases or disorders disclosed herein, examples of which include, but are not limited to, depression (e.g., MDD), inflammation, pain, and neuroinflammation.

[0614] The compounds of the present disclosure (e.g., a compound of Formula (I) through (VII), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof), may be used for a maintenance regimen. As used herein, a “maintenance regimen” generally refers to the administration of the compounds of the present disclosure (e.g., a compound of Formula (I) through (VII), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof) following achievement of a target dose, e.g., following completion of an up-titration regimen, and / or following a positive clinical response, e.g., improvement of the patient's condition, either to the same drug or to a different drug. In some embodiments, the patient is administered a first drug for a therapeutic regimen and a second drug for a maintenance regimen, wherein the first and second drugs are different. For example, the patient may be administered a therapeutic regimen of a first drug which is not a compound of the present disclosure (e.g., the first drug is a serotonergic psychedelic such as LSD, psilocybin, MDMA, dimethyltryptamine, etc., or a non-psychedelic drug), followed by a compound of the present disclosure (as the second drug) in a maintenance regimen. In another example, a different compound of the present disclosure is used for the therapeutic regimen (first drug) than is used for the maintenance regimen (second drug). In some embodiments, the patient is administered the same compound of the present disclosure for both a therapeutic regimen and a maintenance regimen. In any case, the maintenance dose of the compounds of the present disclosure may be used to ‘maintain’ the therapeutic response and / or to prevent occurrences of relapse. When the same compound of the present disclosure is used for both the original therapeutic regimen and for the maintenance regimen, the maintenance dose of the compound may be at or below the therapeutic dose. In some embodiments, the maintenance dose is a psychedelic dose. In some embodiments, the maintenance dose is a sub-psychedelic dose. Generally, dosing is carried out daily or intermittently for the maintenance regimen, however, maintenance regimens can also be carried out continuously, for example, over several days, weeks, months, or years. Moreover, the maintenance dose may be given to a patient over a long period of time, even chronically.

[0615] The subjects treated herein may have a disease or disorder associated with a serotonin 5-HT2 receptor.

[0616] In some embodiments, the disease or disorder is a neuropsychiatric disease or disorder or an inflammatory disease or disorder. In some embodiments, the neuropsychiatric disease or disorder is not schizophrenia or cognitive deficits in schizophrenia.

[0617] In some embodiments, the disease or disorder is a central nervous system (CNS) disorder, including, but not limited to, major depressive disorder (MDD), treatment-resistant depression (TRD), post-traumatic stress disorder (PTSD), bipolar and related disorders (including, but not limited to, bipolar I disorder, bipolar II disorder, cyclothymic disorder), obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social anxiety disorder, substance use disorders (including, but not limited to, alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, smoking, and cocaine use disorder), eating disorders (including, but not limited to anorexia nervosa, bulimia nervosa, binge-eating disorder, etc.), Alzheimer's disease, cluster headache and migraine, attention deficit hyperactivity disorder (ADHD), pain and neuropathic pain, aphantasia, childhood-onset fluency disorder, major neurocognitive disorder, mild neurocognitive disorder, suicidal ideation, suicidal behavior, major depressive disorder with suicidal ideation or suicidal behavior, melancholic depression, atypical depression, dysthymia, non-suicidal self-injury disorder (NSSID), chronic fatigue syndrome, Lyme disease, gambling disorder, paraphilic disorders (including, but not limited to, pedophilic disorder, exhibitionistic disorder, voyeuristic disorder, fetishistic disorder, sexual masochism or sadism disorder, and transvestic disorder, etc.), sexual dysfunction (e.g., low libido, hypoactive sexual desire disorder (HSDD), etc.), peripheral neuropathy, and obesity.

[0618] In some embodiments, the methods provided herein are used to treat a subject with a depressive disorder. As used herein, the terms “depressive disorder” or “depression” refers to a group of disorders characterized by low mood that can affect a person's thoughts, behavior, feelings, and sense of well-being lasting for a period of time. In some embodiments, the depressive disorder disrupts the physical and psychological functions of a person. In some embodiments, the depressive disorder causes a physical symptom such as weight loss, aches or pains, headaches, cramps, or digestive problems. In some embodiments, the depressive disorder causes a psychological symptom such as persistent sadness, anxiety, feelings of hopelessness and irritability, feelings of guilt, worthlessness, or helplessness, loss of interest or pleasure in hobbies and activities, difficulty concentrating, remembering, or making decisions. In some embodiments, the depressive disorder is major depressive disorder (MDD), atypical depression, bipolar disorder, catatonic depression, depressive disorder due to a medical condition, postpartum depression, premenstrual dysphoric disorder, seasonal affective disorder, or treatment-resistant depression (TRD).

[0619] In some embodiments, the disease or disorder is major depressive disorder (MDD). As used herein, the term “major depressive disorder” refers to a condition characterized by a time period of low mood that is present across most situations. Major depressive disorder is often accompanied by low self-esteem, loss of interest in normally enjoyable activities, low energy, and pain without a clear cause. In some instances, major depressive order is characterized by symptoms of depression lasting at least two weeks. In some instances, an individual experiences periods of depression separated by years. In some instances, an individual experiences symptoms of depression that are nearly always present. Major depressive disorder can negatively affect a person's personal, work, or school life, as well as sleeping, eating habits, and general health. Approximately 2-7% of adults with major depressive disorder commit suicide, and up to 60% of people who commit suicide had major depressive disorder or another related mood disorder. Dysthymia is a subtype of major depressive disorder consisting of the same cognitive and physical problems as major depressive disorder with less severe but longer-lasting symptoms. Exemplary symptoms of a major depressive disorder include, but are not limited to, feelings of sadness, tearfulness, emptiness or hopelessness, angry outbursts, irritability or frustration, even over small matters, loss of interest or pleasure in most or all normal activities, sleep disturbances, including insomnia or sleeping too much, tiredness and lack of energy, reduced appetite, weight loss or gain, anxiety, agitation or restlessness, slowed thinking, speaking, or body movements, feelings of worthlessness or guilt, fixating on past failures or self-blame, trouble thinking, concentrating, making decisions, and remembering things, frequent thoughts of death, suicidal thoughts, suicide attempts, or suicide, and unexplained physical problems, such as back pain or headaches.

[0620] As used herein, the term “atypical depression” refers to a condition wherein an individual shows signs of mood reactivity (i.e., mood brightens in response to actual or potential positive events), significant weight gain, increase in appetite, hypersomnia, heavy, leaden feelings in arms or legs, and / or long-standing pattern of interpersonal rejection sensitivity that results in significant social or occupational impairment. Exemplary symptoms of atypical depression include, but are not limited to, daily sadness or depressed mood, loss of enjoyment in things that were once pleasurable, major changes in weight (gain or loss) or appetite, insomnia or excessive sleep almost every day, a state of physical restlessness or being rundown that is noticeable by others, daily fatigue or loss of energy, feelings of hopelessness, worthlessness, or excessive guilt almost every day, problems with concentration or making decisions almost every day, recurring thoughts of death or suicide, suicide plan, or suicide attempt.

[0621] As used herein, the term “bipolar disorder” refers to a condition that causes an individual to experience unusual shifts in mood, energy, activity levels, and the ability to carry out day-to day tasks. Individuals with bipolar disorder experience periods of unusually intense emotion, changes in sleep patterns and activity levels, and unusual behaviors. These distinct periods are called “mood episodes.” Mood episodes are drastically different from the moods and behaviors that are typical for the person. Exemplary symptoms of mania, excessive behavior, include, but are not limited to, abnormally upbeat, jumpy, or wired behavior; increased activity, energy, or agitation, exaggerated sense of well-being and self-confidence, decreased need for sleep, unusual talkativeness, racing thoughts, distractibility, and poor decision-making—for example, going on buying sprees, taking sexual risks, or making foolish investments. Exemplary symptoms of depressive episodes or low mood, include, but are not limited to, depressed mood, such as feelings of sadness, emptiness, hopelessness, or tearfulness; marked loss of interest or feeling no pleasure in all-or almost all-activities, significant weight loss, weight gain, or decrease or increase in appetite, insomnia or hypersomnia (excessive sleeping or excessive sleepiness), restlessness or slowed behavior, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, decreased ability to think or concentrate, or indecisiveness, and thinking about, planning or attempting suicide. Bipolar disorder includes bipolar I disorder, bipolar II disorder, and cyclothymic disorder. Bipolar I disorder is defined by manic episodes that last at least 7 days or by severe manic symptoms that require hospitalization. A subject with bipolar I disorder may also experience depressive episodes typically lasting at least 2 weeks. Episodes of depression with mixed features, i.e., depressive and manic symptoms at the same time, are also possible. Bipolar II disorder is characterized by a pattern of depressive and hypomanic episodes, but not severe manic episodes typical of bipolar I disorder. Cyclothymic disorder (also referred to as cyclothymia) is characterized by periods of hypomanic symptoms (elevated mood and euphoria) and depressive symptoms lasting over a period of at least 2 years. The mood fluctuations are not sufficient in number, severity, or duration to meet the full criteria for a hypomanic or depressive episode.

[0622] As used herein, the term “catatonic depression” refers to a condition causing an individual to remain speechless and motionless for an extended period. Exemplary symptoms of catatonic depression include, but are not limited to, feelings of sadness, which can occur daily, a loss of interest in most activities, sudden weight gain or loss, a change in appetite, trouble falling asleep, trouble getting out of bed, feelings of restlessness, irritability, feelings of worthlessness, feelings of guilt, fatigue, difficulty concentrating, difficulty thinking, difficulty making decisions, thoughts of suicide or death, and / or a suicide attempt.

[0623] As used herein, the term “depressive disorder due to a medical condition” refers to a condition wherein an individual experiences depressive symptoms caused by another illness. Examples of medical conditions known to cause a depressive disorder include, but are not limited to, HIV / AIDS, diabetes, arthritis, strokes, brain disorders such as Parkinson's disease, Huntington's disease, multiple sclerosis, and Alzheimer's disease, metabolic conditions (e.g., vitamin B12 deficiency), autoimmune conditions (e.g., lupus and rheumatoid arthritis), viral or other infections (hepatitis, mononucleosis, herpes), back pain, and cancer (e.g., pancreatic cancer).

[0624] As used herein, the term “postpartum depression” refers to a condition as the result of childbirth and hormonal changes, psychological adjustment to parenthood, and / or fatigue. Postpartum depression is often associated with women, but men can also suffer from postpartum depression as well. Exemplary symptoms of postpartum depression include, but are not limited to, feelings of sadness, hopeless, emptiness, or overwhelmed; crying more often than usual or for no apparent reason; worrying or feeling overly anxious; feeling moody, irritable, or restless; oversleeping, or being unable to sleep even when the baby is asleep; having trouble concentrating, remembering details, and making decisions; experiencing anger or rage; losing interest in activities that are usually enjoyable; suffering from physical aches and pains, including frequent headaches, stomach problems, and muscle pain; eating too little or too much; withdrawing from or avoiding friends and family; having trouble bonding or forming an emotional attachment with the baby; persistently doubting his or ability to care for the baby; and thinking about harming themselves or the baby.

[0625] As used herein, the term “premenstrual dysphoric disorder” refers to a condition wherein an individual expresses mood lability, irritability, dysphoria, and anxiety symptoms that occur repeatedly during the premenstrual phase of the cycle and remit around the onset of menses or shortly thereafter. Exemplary symptoms of premenstrual dysphoric disorder includes, but are not limited to, lability (e.g., mood swings), irritability or anger, depressed mood, anxiety and tension, decreased interest in usual activities, difficulty in concentration, lethargy and lack of energy, change in appetite (e.g., overeating or specific food cravings), hypersomnia or insomnia, feeling overwhelmed or out of control, physical symptoms (e.g., breast tenderness or swelling, joint or muscle pain, a sensation of ‘bloating’ and weight gain), self-deprecating thoughts, feelings of being keyed up or on edge, decreased interest in usual activities (e.g., work, school, friends, hobbies), subjective difficulty in concentration, and easy fatigability.

[0626] As used herein, the term “seasonal affective disorder” refers to a condition wherein an individual experiences mood changes based on the time of the year. In some instances, an individual experiences low mood, low energy, or other depressive symptoms during the fall and / or winter season. In some instances, an individual experiences low mood, low energy, or other depressive symptoms during the spring and / or summer season. Exemplary symptoms of seasonal affective disorder include, but are not limited to, feeling depressed most of the day or nearly every day, losing interest in activities once found enjoyable, having low energy, having problems with sleeping, experiencing changes in appetite or weight, feeling sluggish or agitated, having difficulty concentrating, feeling hopeless, worthless, or guilty, and having frequent thoughts of death or suicide.

[0627] In some embodiments, a depressive disorder comprises a medical diagnosis based on the criteria and classification from Diagnostic and Statistical Manual of Mental Disorders, 5th Ed. In some embodiments, a depressive disorder comprises a medical diagnosis based on an independent medical evaluation.

[0628] In some embodiments, the methods described herein are provided to a subject with depression that is resistant to treatment. In some embodiments, the subject has been diagnosed with treatment-resistant depression (TRD). The term “treatment-resistant depression” refers to a kind of depression that does not respond or is resistant to at least one or more treatment attempts of adequate dose and duration. In some embodiments, the subject with treatment-resistant depression has failed to respond to 1 treatment attempt, 2 treatment attempts, 3 treatment attempts, 4 treatment attempts, 5 treatment attempts, or more. In some embodiments, the subject with treatment-resistant depression has been diagnosed with major depressive disorder and has failed to respond to 3 or more treatment attempts. In some embodiments, the subject with treatment resistant depression has been diagnosed with bipolar disorder and has failed to respond to 1 treatment attempt.

[0629] In some embodiments, the methods provided herein reduce at least one sign or symptom of a depressive disorder. In some embodiments, the methods provided herein reduce at least one sign or symptom of a depressive disorder by between about 5% and about 100%, for example, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, or more, compared to prior to treatment.

[0630] In some embodiments, the disease or disorder is an anxiety disorder. As used herein, the term “anxiety disorder” refers to a state of apprehension, uncertainty, and / or fear resulting from the anticipation of an event and / or situation. Anxiety disorders cause physiological and psychological signs or symptoms. Non-limiting examples of physiological symptoms include muscle tension, heart palpitations, sweating, dizziness, shortness of breath, tachycardia, tremor, fatigue, worry, irritability, and disturbed sleep. Non-limiting examples of psychological symptoms include fear of dying, fear of embarrassment or humiliation, fear of an event occurring, etc. Anxiety disorders also impair a subject's cognition, information processing, stress levels, and immune response. In some embodiments, the methods disclosed herein treat chronic anxiety disorders. As used herein, a “chronic” anxiety disorder is recurring. Examples of anxiety disorders include, but are not limited to, generalized anxiety disorder (GAD), social anxiety disorder, panic disorder, panic attack, a phobia-related disorder (e.g., phobias related to flying, heights, specific animals such as spiders / dogs / snakes, receiving injections, blood, etc., agoraphobia), separation anxiety disorder, selective mutism, anxiety due to a medical condition, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), substance-induced anxiety disorder, etc.

[0631] In some embodiments, the subject in need thereof develops an anxiety disorder after experiencing the effects of a disease. The effects of a disease include diagnosis of an individual with said disease, diagnosis of an individual's loved ones with said disease, social isolation due to said disease, quarantine from said disease, or social distancing as a result of said disease. In some embodiments, an individual is quarantined to prevent the spread of the disease. In some embodiments, the disease is COVID-19, SARS, or MERS. In some embodiments, a subject develops an anxiety disorder after job loss, loss of housing, or fear of not finding employment.

[0632] In some embodiments, the disease or disorder is generalized anxiety disorder (GAD). Generalized anxiety disorder is characterized by excessive anxiety and worry, fatigue, restlessness, increased muscle aches or soreness, impaired concentration, irritability, and / or difficulty sleeping. In some embodiments, a subject with generalized anxiety disorder does not have associated panic attacks. In some embodiments, the subject has generalized anxiety disorder with depression. In some embodiments, the methods herein are provided to a subject with generalized anxiety disorder also having symptoms of depression. In some embodiments, after treating the symptom is reduced compared to prior to treating by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.

[0633] In some embodiments, the disease or disorder is social anxiety disorder. As used herein, “social anxiety disorder” is a marked fear or anxiety about one or more social situations in which the individual is exposed to possible scrutiny by others. Non-limiting examples of situations which induce social anxiety include social interactions (e.g., having a conversation, meeting unfamiliar people), being observed (e.g., eating or drinking), and performing in front of others (e.g., giving a speech). In some embodiments, the social anxiety disorder is restricted to speaking or performing in public. In some embodiments, treating according to the methods of the disclosure reduces or ameliorates a symptom of social anxiety disorder. In some embodiments, after treating the symptom is reduced compared to prior to treating by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.

[0634] In some embodiments, the disease or disorder is a compulsive disorder, such as obsessive-compulsive disorder (OCD), body-focused repetitive behavior, hoarding disorder, gambling disorder, compulsive buying, compulsive internet use, compulsive video gaming, compulsive sexual behavior, compulsive eating, compulsive exercise, body dysmorphic disorder, hoarding disorder, dermatillomania, trichotillomania, excoriation, substance-induced obsessive compulsive and related disorder, or an obsessive-compulsive disorder due to another medical condition, etc., or a combination thereof. In some embodiments, the disease or disorder is obsessive-compulsive disorder (OCD).

[0635] In some embodiments, at least one sign or symptom of an anxiety disorder is improved following the administration of a compound as disclosed herein. In some embodiments, a sign or symptom of an anxiety disorder is measured according to a diary assessment, an assessment by a clinician or caregiver, or a clinical scale. In some embodiments, treatment causes a demonstrated improvement in one or more of the following: State-Trait Anxiety Inventory (STAI), Beck Anxiety Inventory (BAI), Hospital Anxiety and Depression Scale (HADS), Generalized Anxiety Disorder questionnaire-IV (GADQ-IV), Hamilton Anxiety Rating Scale (HARS), Leibowitz Social Anxiety Scale (LSAS), Overall Anxiety Severity and Impairment Scale (OASIS), Hospital Anxiety and Depression Scale (HADS), Patient Health Questionnaire 4 (PHQ-4), Social Phobia Inventory (SPIN), Brief Trauma Questionnaire (BTQ), Combat Exposure Scale (CES), Mississippi Scale for Combat-Related PTSD (M-PTSD), Posttraumatic Maladaptive Beliefs Scale (PMBS), Perceived Threat Scale (DRRI-2 Section: G), PTSD Symptom Scale-Interview for DSM-5 (PSS-I-5), Structured Interview for PTSD (SI-PTSD), Davidson Trauma Scale (DTS), Impact of Event Scale-Revised (IES-R), Posttraumatic Diagnostic Scale (PDS-5), Potential Stressful Events Interview (PSEI), Stressful Life Events Screening Questionnaire (SLESQ), Spielberger's Trait and Anxiety, Generalized Anxiety Dis-order 7-Item Scale, The Psychiatric Institute Trichotillomania Scale (PITS), The MGH Hairpulling Scale (MGH-HPS), The NIMH Trichotillomania Severity Scale (NIMH-TSS), The NIMH Trichotillomania Impairment Scale (NIMH-TIS), The Clinical Global Impression (CGI), the Brief Social Phobia Scale (BSPS), The Panic Attack Questionnaire (PAQ), Panic Disorder Severity Scale, Florida Obsessive-Compulsive Inventory (FOCI), The Leyton Obsessional Inventory Survey Form, The Vancouver Obsessional Compulsive Inventory (VOCI), The Schedule of Compulsions, Obsessions, and Pathological Impulses (SCOPI), Padua Inventory-Revised (PI-R), Quality of Life (QoL), The Clinical Global Improvement (CGI) scale, The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), The Yale-Brown Obsessive-Compulsive Scale Second Edition (Y-BOCS-II), The Dimensional Yale-Brown Obsessive-Compulsive Scale (DY-BOCS), The National Institute of Mental Health-Global Obsessive-Compulsive Scale (NIMH-GOCS), The Yale-Brown Obsessive-Compulsive Scale Self-Report (Y-BOCS-SR), The Obsessive-Compulsive Inventory-Re-vised (OCI-R), and the Dimensional Obsessive-Compulsive Scale (DOCS), or a combination thereof. In some embodiments, treating according to the methods of the disclosure results in an improvement in an anxiety disorder compared to pre-treatment of about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, according to any one of the diary assessments, assessments by a clinical or caregiver, or clinical scales, described herein or known in the art.

[0636] In some embodiments, the disease or disorder is attention deficit disorder (ADD). ADD is most commonly diagnosed in children under the age of 16 who have 6 or more symptoms of inattention (5 or more for older teenagers) for at least 6 consecutive months, but no signs of hyperactivity / impulsivity. The symptoms of inattention include, but are not limited to, trouble paying attention, avoids long mental tasks such as homework, trouble staying on task, disorganized or forgetful, doesn't appear to listen when spoken to, doesn't pay close attention to details. Loses things often, makes careless mistakes, and struggles to follow through with instructions. In some embodiments, the disease or disorder is attention deficit hyperactivity disorder (ADHD). ADHD is marked by an ongoing pattern of inattention and / or hyperactivity-impulsivity. Hyperactivity-impulsivity symptoms may often include, but are not limited to, fidgeting or squirming while seated, leaving their seats in situations where staying seated is expected, running, dashing, or climbing around at inappropriate times, being unable to engage in hobbies quietly, being constantly in motion, talking excessively, answering questions before they are fully asked, having difficulty waiting for one's turn, and interrupting or intruding on others during conversations or activities.

[0637] In some embodiments, the disease or disorder is a headache disorder. As used herein, the term “headache disorder” refers to a disorder characterized by recurrent headaches. Headache disorders include migraine, tension-type headache, cluster headache, and chronic daily headache syndrome.

[0638] In some embodiments, a method of treating cluster headaches in a subject in need thereof is disclosed herein. In some embodiments, at least one sign or symptom of cluster headache is improved following treatment. In some embodiments, the sign or symptom of cluster headache is measured according to a diary assessment, a physical or psychological assessment by clinician, an imaging test, or a neurological examination. Cluster headache is a primary headache disorder and belongs to the trigeminal autonomic cephalalgias. The definition of cluster headaches is a unilateral headache with at least one autonomic symptom ipsilateral to the headache. Attacks are characterized by severe unilateral pain predominantly in the first division of the trigeminal nerve-the fifth cranial nerve whose primary function is to provide sensory and motor innervation to the face. Attacks are also associated with prominent unilateral cranial autonomic symptoms and subjects often experience agitation and restlessness during attacks. In some embodiments, a subject with cluster headaches also experiences nausea and / or vomiting. In some embodiments, a subject with cluster headaches experiences unilateral pain, excessive tearing, facial flushing, a droopy eyelid, a constricted pupil, eye redness, swelling under or around one or both eyes, sensitivity to light, nausea, agitation, and restlessness.

[0639] In some embodiments, a method of treating migraines in a subject in need thereof is disclosed herein. A migraine is a moderate to severe headache that affects one half or both sides of the head, is pulsating in nature, and last from 2 to 72 hours. Symptoms of migraine include headache, nausea, sensitivity to light, sensitivity to sound, sensitivity to smell, dizziness, difficulty speaking, vertigo, vomiting, seizure, distorted vision, fatigue, or loss of appetite. Some subjects also experience a prodromal phase, occurring hours or days before the headache, and / or a postdromal phase following headache resolution. Prodromal and postdromal symptoms include hyperactivity, hypoactivity, depression, cravings for particular foods, repetitive yawning, fatigue and neck stiffness and / or pain. In some embodiments, the migraine is a migraine without aura, a migraine with aura, a chronic migraine, an abdominal migraine, a basilar migraine, a menstrual migraine, an ophthalmoplegic migraine, an ocular migraine, an ophthalmic migraine, or a hemiplegic migraine. In some embodiments, the migraine is a migraine without aura. A migraine without aura involves a migraine headache that is not accompanied by a headache. In some embodiments, the migraine is a migraine with aura. A migraine with aura is primarily characterized by the transient focal neurological symptoms that usually precede or sometimes accompany the headache. Less...

Claims

1. A compound having a structure of Formula (I):or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof,wherein:X1 and X2 are independently hydrogen or deuterium;Y1 and Y2 are independently hydrogen or deuterium;R3 is hydrogen or deuterium;R4 is —SCF2H, —SCFH2, —SCH2CF2CF2H, —OCF3, —OCF2H, —OCFH2, —OCH2CF2CF2H, -cyclopentyl (—C5H9), or -A(CF2)m(CH2)nQ, wherein A is S, O, CH2, or CF2, m is 0 to 3, n is 0 to 6, and Q is —C≡CH or —C≡N;R6 and R7 are independently hydrogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; or alternatively R6 and R7 together with the nitrogen atom attached thereto are optionally joined to form a substituted or unsubstituted heterocycloalkyl; andeach Ra is independently a substituted or unsubstituted C1-C6 alkyl.

2. The compound of claim 1, wherein Y1 and Y2 are hydrogen.

3. The compound of claim 1, wherein R3 is hydrogen.

4. The compound of claim 1, wherein X1 and X2 are hydrogen.

5. The compound of claim 1, wherein X1 and X2 are deuterium.

6. The compound of claim 1, wherein each Ra is —CH3 or —CD3.

7. The compound of claim 1, wherein R4 is —SCF2H, —SCH2CF2CF2H, or —SCH2CH2CH2C≡CH.

8. The compound of claim 1, having a structure of Formula (II):or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof,wherein:X1 and X2 are independently hydrogen or deuterium;Y1 and Y2 are independently hydrogen or deuterium; andR4 is —SCF2H, —SCFH2, —SCH2CF2CF2H, —OCF3, —OCF2H, —OCFH2, —OCH2CF2CF2H, -cyclopentyl (—C5H9), or -A(CF2)m(CH2)nQ, wherein A is S, O, CH2, or CF2, m is 0 to 3, n is 0 to 6, and Q is —C≡CH or —C≡N.

9. The compound of claim 8, wherein X1 and X2 are hydrogen.

10. The compound of claim 8, wherein R4 is —SCF2H, —SCH2CF2CF2H, or —SCH2CH2CH2C≡CH.

11. The compound of claim 8, wherein R4 is —SCF2H.12-14. (canceled)15. The compound of claim 1, having a structure of Formula (IV):or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof,wherein:Y1 and Y2 are independently hydrogen or deuterium;R4 is —SCF2H, —SCFH2, —SCH2CF2CF2H, —OCF3, —OCF2H, —OCFH2, —OCH2CF2CF2H, -cyclopentyl (—C5H9), or -A(CF2)m(CH2)nQ, wherein A is S, O, CH2, or CF2, m is 0 to 3, n is 0 to 6, and Q is —C≡CH or —C≡N; andeach Ra is independently a substituted or unsubstituted C1-C6 alkyl.

16. A compound having a structure of Formula (V):or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof,wherein:X1 and X2 are independently hydrogen or deuterium;Y1 and Y2 are independently hydrogen or deuterium;R4 is halogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C3-C10 cycloalkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, —ORb, or —SRb;R6 is hydrogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl;R7 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl;or alternatively R6 and R7 together with the nitrogen atom attached thereto are optionally joined to form a substituted or unsubstituted heterocycloalkyl;each Ra is independently a substituted or unsubstituted C1-C6 alkyl; andRb is hydrogen, deuterium, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, or a substituted or unsubstituted C3-C10 cycloalkyl;with the proviso that at least one of X1, X2, Y1, Y2, R3, R4, R6, R7, and Ra comprises deuterium and / or R4 is selected from the group consisting of —SCF3, —SCF2H, —SCFH2, —SCH2CH2CF3, —SCH2CH2CF2H, —SCH2CH2CFH2, —SCH2CF2CF2H, —OCF3, —OCF2H, —OCFH2, —OCH2CH2CF3, —OCH2CH2CF2H, —OCH2CH2CFH2, —OCH2CF2CF2H, -cyclopentyl (—C5H9), and -A(CF2)m(CH2)nQ, wherein A is S, O, CH2, or CF2, m is 0 to 3, n is 0 to 6, and Q is —C≡CH or —C≡N.

17. The compound of claim 16, wherein R6 is hydrogen, and R7 is an unsubstituted C1-C6 alkyl, a C1-C6 alkyl substituted with one or more deuterium atoms, a C1-C6 alkyl substituted with one or more fluorine atoms, or a C1-C6 alkyl substituted with a substituted or unsubstituted cycloalkyl.

18. The compound of claim 16, which is selected from the group consisting ofor a pharmaceutically acceptable salt, solvate, or prodrug thereof.19-96. (canceled)97. A compound having a structure of Formula (VI):or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof,wherein:X1 and X2 are independently hydrogen or deuterium;Y1 and Y2 are independently hydrogen or deuterium;R3 is hydrogen or deuterium;R6 and R7 are independently hydrogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; or alternatively R6 and R7 together with the nitrogen atom attached thereto are optionally joined to form a substituted or unsubstituted heterocycloalkyl;each Ra is independently a substituted or unsubstituted C1-C6 alkyl; andeach Rb is independently a substituted or unsubstituted C1-C2 alkyl; or alternatively two Rbs together with the carbon atom attached thereto are optionally joined to form a substituted or unsubstituted cycloalkyl.

98. The compound of claim 97, which is selected from the group consisting ofor a pharmaceutically acceptable salt, solvate, or prodrug thereof.99-100. (canceled)101. A compound having a structure of Formula (VII):or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof,wherein:X1 and X2 are independently hydrogen or deuterium;Y1 and Y2 are independently hydrogen or deuterium;R6 is hydrogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl;R7 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl;or alternatively R6 and R7 together with the nitrogen atom attached thereto are optionally joined to form a substituted or unsubstituted heterocycloalkyl;each Ra is independently a substituted or unsubstituted C1-C6 alkyl; andRb is hydrogen, deuterium, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, or a substituted or unsubstituted C3-C10 cycloalkyl.

102. The compound of claim 101, which is selected from the group consisting ofor a pharmaceutically acceptable salt, solvate, or prodrug thereof.103-104. (canceled)

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